Organic LED light and ultrasonic transducer device in a flexible layer configuration with electrical stimulation

ABSTRACT

A flexible device having a layered structure for delivering electrical stimulation and one or both of light and ultrasound to a skin surface is provided. The device is flexible so as to form a non-planar contact surface against the skin surface, and includes one or both of (a) a flexible light emitter layer positioned between two flexible conductive layers that emits light when driven by a power source and (b) a flexible ultrasound emitter layer positioned between two flexible conductive layers that produces ultrasound when driven by a power source. The device also includes a flexible electrical stimulation layer that functions as an electrode and is configured to provide electrical stimulation when driven by a power source.

CROSS-REFERENCE TO RELATED APPLICATIONS

This continuation application is based on and claims priority to U.S.patent application Ser. No. 14/213,999, filed on Mar. 14, 2014, whichclaims priority to U.S. Provisional Application Ser. No. 61/799,153,filed on Mar. 15, 2013, each of which is incorporated herein byreference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

BACKGROUND OF THE INVENTION

Various devices for delivering light and/or ultrasound to the skin of apatient for therapeutic or cosmetic purposes are known in the art. Ingeneral, these devices do not provide uniform light and/or a uniformultrasound field across the surface of the device. For example, whenconventional light emitting diodes (LEDs) are used as a light source,each LED operates as a point source that can generate a hot spot ifpositioned too close to the patient's skin. Also, because typical LEDshave a relatively large beam divergence (e.g., about 65 degrees on eachside for a total of 130 degrees), the light field is not uniform unlessthe LEDs are positioned a sufficient distance from the tissue. Asanother example, many conventional ultrasonic transducers have a beamnon-uniformity ratio (i.e., the ratio between peak intensity and averageintensity in the beam) of 5 to 6 or higher. As a result, the intensityof the ultrasound varies across the surface of the device.

BRIEF SUMMARY OF THE INVENTION

A device for delivering light and ultrasound across a skin surface isprovided. The device has a layered structure comprising a light sourceand an ultrasonic transducer supported by a substrate. The light sourcecomprises a flexible light emitter layer electrically coupled to a firstconductive layer and a second conductive layer, wherein at least one ofthe first and second conductive layers is transparent. The ultrasonictransducer comprises a flexible ultrasound emitter layer electricallycoupled to a third conductive layer and a fourth conductive layer. In anexemplary embodiment, the light source comprises one of an organic lightemitting diode or a plurality of printed light emitting diodes and theultrasonic transducer comprises a piezoelectric coating (film or paint).The device may optionally include a flexible transparent heater layerand/or an electrical stimulation layer. Preferably, the device is verythin and has a thickness of about 3 mm or less, and is flexible andconformable so as to form a non-planar contact surface against the skinsurface.

The light source produces light with an intensity that is substantiallyuniform across the surface of the device. Similarly, the ultrasonictransducer produces ultrasound with an intensity that is substantiallyuniform across the surface of the device. Preferably, the ultrasoundproduced across the surface of the device has a beam non-uniformityratio of 3 or lower. The ultrasonic transducer produces low frequencyultrasound at a frequency in the range of 2 kHz to 500 kHz and/or highfrequency ultrasound at a frequency in the range of 500 kHz to 20 MHz.In one embodiment, the ultrasonic transducer is a dual frequencyultrasound transducer that produces both low frequency ultrasound andhigh frequency ultrasound either simultaneously or sequentially. Thelight source and ultrasonic transducer are capable of delivering lightand ultrasound, respectively, in a pulsed mode or a continuous mode.

In some embodiments, the device is electronically coupled to acontroller, which is also electrically coupled to one or more sensors.The controller is operable to receive sensor data from the sensor anddynamically control the device in response to the received sensor data.In one embodiment, the controller dynamically adjusts an operatingparameter of the device in response to the received sensor data. Forexample, the controller may independently control the light source byadjusting the activation and deactivation of the light source, voltage,current, light wavelength, pulse width, modulation frequency, dutyfactor, or light treatment time. As another example, the controller mayindependently control the ultrasonic transducer by adjusting theactivation and deactivation of the transducer, ultrasound treatmenttime, ultrasound frequency, or ultrasound modulation frequency.

In some embodiments, the controller is electrically coupled to acommunication module that enables wired or wireless communication withan external control device. The external control device may comprise,for example, a smart phone, a tablet computer, or a laptop computer. Theexternal control device is capable of executing a control applicationfor externally controlling the controller. The external control devicemay in turn communicate over a communication network (e.g., the Internetcloud) in order to access applications or data hosted on a remote serverto modify one or more treatment parameters based on information storedon the remote server.

In a preferred aspect, the light and ultrasound emitted from the devicecauses transdermal transport of a therapeutic or cosmetic compositionthrough the skin surface. In one embodiment, the therapeutic or cosmeticcomposition includes one or more of large or small molecular weighthyaluronic acid, ascorbic acid (vitamin C) or alpha-tocopherol (vitaminE) or their derivatives or their pharmaceutically acceptable salts andesters.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the general structure of a device that provides lightand ultrasound in the form of a very thin layered structure inaccordance with the present invention.

FIG. 2 is a top plan view of various exemplary shapes for the device ofthe present invention.

FIG. 3A illustrates an exemplary OLED structure for use in the device ofthe present invention.

FIG. 3B illustrates an exemplary printable LED structure for use in thedevice of the present invention.

FIG. 4 illustrates a first exemplary embodiment of a device inaccordance with the present invention.

FIG. 5 illustrates a second exemplary embodiment of a device inaccordance with the present invention.

FIG. 6 illustrates a third exemplary embodiment of a device inaccordance with the present invention.

FIG. 7 illustrates a fourth exemplary embodiment of a device inaccordance with the present invention.

FIG. 8 illustrates a fifth exemplary embodiment of a device inaccordance with the present invention.

FIG. 9 illustrates a sixth exemplary embodiment of a device inaccordance with the present invention.

FIG. 10 illustrates a seventh exemplary embodiment of a device inaccordance with the present invention.

FIG. 11 illustrates an eighth exemplary embodiment of a systemcomprising a plurality of the devices of the present invention arrangedin an array.

FIG. 12 is a block diagram of a first exemplary electronic circuit forcontrolling the device of the present invention, which includes aninternal control module that is preprogrammed to provide a fixed dose.

FIG. 13 is a block diagram of a second exemplary electronic circuit forcontrolling the device of the present invention, which includes anexternal control module that enables manual adjustment of the deviceparameters.

FIG. 14 is a block diagram of a third exemplary electronic circuit forcontrolling the device of the present invention, which includes sensorsthat provide feedback to enable automatic adjustment of the deviceparameters.

FIG. 15 is a block diagram of a fourth exemplary electronic circuit forcontrolling a plurality of the devices of the present invention arrangedin an array.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The present invention is directed to a flexible device that provideslight energy and/or ultrasound in the form of a very thin layeredstructure. The overall thickness of the device is typically about 10 mmor less (e.g., about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2,0.1, 0.05 mm or less). The device comprises at least one flexible lightsource for providing light and/or at least one flexible ultrasonictransducer for providing ultrasound. Among other things, the device canbe used for transdermal drug delivery, cosmetic applications, andskin/wound healing. An advantage of the device is that the light energyand/or ultrasound produced by the device is substantially constantacross the surface of the device. Another advantage is that the deviceis flexible and may be contoured in any shape and size allowing thedevice to conform to any body surface due to the layered/stacked natureof the films/layers forming the light source and/or ultrasonictransducer of the device. A further advantage of the device is that iscan be manufactured at a relatively low cost and, thus, the device maybe disposable. The device may optionally be controlled by an electroniccircuit with one or more sensors that operate in a closed loop toprovide feedback to a microcontroller for dose control.

FIG. 1 illustrates the basic elements of the device of the presentinvention in the form of a thin layered structure. The device 10comprises a light source 12 and an ultrasonic transducer 14. The lightsource 12 comprises a flexible light emitter 40 located between an anode50 and a cathode 60. The ultrasonic transducer 14 comprises a flexibleultrasound emitter 30 located between the cathode 60 and an anode 70.The cathode 60 is a common cathode for both the light source 12 and theultrasonic transducer 14. Suitable power sources are connected to thedevice 10. Preferably, direct current (DC) or pulsed DC is used to powerthe light source 12, while alternating current (AC) is used to power theultrasonic transducer 14.

The light source of the present invention produces light with anintensity that is substantially constant across the surface of thedevice so as to provide substantially uniform light emission when thedevice is in contact with the patient's skin. As described in moredetail below, the light source may comprise, for example, organic lightemitting diodes (OLEDs) or printable light emitting diodes (LEDs)(organic or inorganic) commonly referred to as LED ink. With OLEDs, theintensity of the light is substantially constant across the surface ofthe device due to the relatively uniform deposition of organic materialon a substrate during fabrication of the OLED. With LED ink, each lightsource is very small which enables the LEDs to be positioned in veryclose proximity to each other. During fabrication, the LEDs may beprinted in a uniform manner whereby each LED operates as a point sourcein which the beams from the individual LEDs are substantially parallelto each other to provide substantially uniform light across the surfaceof the device. Unlike conventional LEDs, the light source of the presentinvention does not need to be positioned a sufficient distance from thepatient's skin in order to deliver a substantially uniform dose oflight. It can also be appreciated that the light source of the presentinvention is capable of decreasing hot spots on the surface of apatient's skin to provide a safer delivery to the patient. Also, asubstantially uniform dose of light across the surface of the deviceensures that all of the tissue is effectively treated with the sametherapeutically effective dose.

The ultrasonic transducer of the present invention produces ultrasoundwith an intensity that is substantially constant across the surface ofthe device so as to provide a substantially uniform ultrasound field. Inone aspect, the ultrasonic transducer has a beam non-uniformity ratio(BNR) (i.e., the ratio between peak intensity and average intensity inthe beam) of 3 or lower (e.g., about 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6,1.4, 1.2, 1 or lower). As described in more detail below, the ultrasonictransducer may comprise, for example, a flexible piezoelectric coating(film or paint). It can be appreciated that the ultrasonic transducer iscapable of decreasing hot spots on the surface of a patient's skin toprovide a safer delivery to the patient. Also, a substantially uniformdose of ultrasound across the surface of the device ensures that all ofthe tissue is effectively treated with the same therapeuticallyeffective dose.

The device may be in the form of a patch, pad, mask, wrap, fiber,bandage or cylinder, for example. The device may have a variety ofshapes and sizes. For example, the device may be square, rectangular,circular, elliptical, clover-shaped, oblong, or crescent/moon-shaped,such as the devices 10 a-10 f generally illustrated in FIG. 2. Theoverall surface area of one side of the device may range from, forexample, 1 cm² to 1 m², although typically the surface area is about 1to 2000 cm² (e.g., about 1, 4, 9, 16, 25, 36, 49, 64, 81, 100, 121, 144,169, 196, 225, 289, 324, 361, 400, 441, 484, 529, 576, 625, 676, 729,784, 841, 900, 961, 1024, 1089, 1156, 122, 1296, 1369, 1444, 1521, 1600,1681, 1764, 1849, 1936 or 2000 cm² or some range therebetween). Thedevice is thus well adapted to be applied to various areas of thepatient's body, for example, the face, eyelids, eyebrows, forehead,lips, mouth, nose, ears, neck as well as the arms, legs, hands, fingers,feet, toes, stomach, and the like.

The total thickness of the device is preferably about 1 cm or less(e.g., about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 cm or less).Most preferably, the total thickness of the device is about 5 mm or less(e.g., about 5, 4.8, 4.6, 4.4, 4.2, 4, 3.8, 3.6, 3.4, 3.2, 3 mm orless).

In one aspect, the device is substantially planar in its form, althoughit is preferably flexible and/or conformable. The device is preferablyflexible and is more preferably conformable such that it may conform tothe contours of the body.

In another aspect, the device is applied to the skin surface for varioustherapies and cosmetic applications. The device may be used inconjunction with a therapeutic and/or cosmetic composition to be appliedto the skin, including gel pads (such as hydrogel pads), lotions, gels,creams, ointments, foams, roll-on formulations, mousses, aerosol andnon-aerosol sprays.

The device may be manufactured by known methods including, for example,spin coating, knife coating, spin casting, drop casting, vapordeposition or sputtering, crystalline growth, patterned etching, dipcoating, or by printing techniques such as screen printing, flexographicprinting, intaglio printing, ink jet printing, 3D printing, off-setting,transfer processes, or by spray applications.

For purposes of description herein, it is to be understood that theinvention may assume various alternative configurations, orientationsand step sequences, except where expressly specified to the contrary. Itis also to be understood that the specific devices and processesdescribed herein and illustrated in the attached drawings are exemplaryembodiments of the present invention. Hence, specific dimensions andother physical characteristics relating to the embodiments disclosedherein are not to be considered as limiting.

As used herein, the singular forms “a,” “an” and “the” include pluralreference unless the context clearly dictates otherwise. Thus, forexample, reference to a “layer” includes aspects having two or more suchlayers unless the context clearly indicates otherwise.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third.As will also be understood by one skilled in the art, all language suchas “up to,” “at least,” and the like include the number recited andrefer to ranges which can be subsequently broken down into subranges asdiscussed above. Finally, as will be understood by one skilled in theart, a range includes each individual member. Thus, for example,reference to 1-3 layers refers to groups having 1, 2, or 3 layers.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described component or element may or may not be present,and that the description includes instances where said component orelement is present and instances where it is not.

The various elements/layers of the device of the present invention willnow be described in more detail.

Substrate

In some exemplary embodiments, the device of the present inventioncomprises a device substrate. The substrate may be any substance capableof supporting the various layers/films of the device. The devicesubstrate is preferably flexible and/or conformable to a surface inwhich the device will be used (e.g., the contours of a patient's body).The device substrate can comprise, for example, an inorganic material,an organic material, or a combination of inorganic and organicmaterials. The device substrate may be, for example, made from metals,plastics or glass. The device substrate may be any shape to support theother components of the device, for example, the device substrate may besubstantially flat or planar, curved, or have portions that aresubstantially flat portions and curved portions. Most preferably, thedevice substrate is transparent, flexible, and conformable in nature.Ideally, the material is a latex-free, non-toxic, non-allergenicmaterial, which is resistant to UV, sunlight and most infection controlproducts.

In exemplary embodiments, the substrate may be comprised of asilicon-based material, rubber, thermoplastic elastomers (TTP), or otherpolymeric material, such as polyester, polyethylene terephthalate (PET),polyethylene naphthalate (PEN), polycarbonate, polystyrene, polyacryl,polyether sulfone (PES), etc. Transparent substrates may include, forexample, polyethylene, ethylene-vinyl acetate copolymers, polyimide(PI), polyetherimide (PEI), ethylene-vinyl alcohol copolymers,polypropylene, polystyrene, polymethyl methacrylate, PVC, polyvinylalcohol, polyvinylbutyral, polyether ether ketone, polysulfone,polyether sulfone, as well as fluoropolymers, such as, fluorinatedethylene-propylene (FEP), tetrafluoroethylene-perfluoroalkyl vinyl ethercopolymers, polyvinyl fluoride, tetrafluoroethylene-ethylene copolymers,tetrafluoroethylene-hexafluoropropylene copolymers,polychlorotrifluoroethylene, polyvinylidene fluoride, polyester,polycarbonate, polyurethanes, polyimide or polyether imide.

In another exemplary embodiment, the transparent substrate is apolyester film, such as Mylar. In another aspect, the substratecomprises a polyetheretherketone film commercially available fromVictrex under the name APTIV. In still another aspect, the substrate isa thin film sold under the name Flexent by Konica Minolta or flexibleglass such as Willow Glass by Dow Corning. Ideally, substrates in director indirect contact with organic layers will have exceptional barriercapabilities that withstand heat, offer flexibility, have sustainedreliability and can be mass produced.

Conductive Layers (Electrodes)

The device of the present invention comprises a plurality of conductivelayers (i.e., electrodes), namely, a cathode and an anode for the lightsource and/or a cathode and an anode for the ultrasonic transducer. Thecathode or anode may comprise a shared electrode such that the sameconductive layer serves as a common cathode or as a common anode forboth the light source and the ultrasonic transducer. In an exemplaryembodiment, the light source and ultrasonic transducer each have ananode and share a common cathode. In this embodiment, the anode for thelight source comprises, for example, a transparent conductive oxide(TCO), such as, but not limited to, indium tin oxide (ITO), zinc oxide(ZnO), and the like. The anode for the ultrasonic transducer and thecommon cathode each comprise, for example, a thin metal film such asaluminum, copper, gold, molybdenum, iridium, magnesium, silver, lithiumfluoride and alloys thereof, or a non-metal conductive layer.

Because the light source must emit light through one or more electrodes,at least one of the electrodes is transparent. The transparent electrodeis positioned on the side of the light source designed to be facing theskin. For a device intended to emit light only through the bottomelectrode (i.e., skin-facing electrode), the top electrode (i.e.,electrode facing away from the skin) does not need to be transparent.The top electrode may thus comprise an opaque or light-reflective metallayer having a high electrical conductivity. Where a top electrode doesnot need to be transparent, using a thicker layer may provide betterconductivity, and using a reflective electrode may increase the amountof light emitted through the transparent electrode by reflecting lightback towards the transparent electrode. Fully transparent light sourcesmay also be fabricated, where both electrodes are transparent.

The thickness of each electrode is typically about 200 nm or less (e.g.,about 200, 180, 160, 140, 120, 100, 90, 80, 70, 60, 50, 40, 30 nm orless). Preferably, the thickness of each electrode is less than 10 nm(e.g., about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.8, 0.6, 0.4, 0.2 nm orless or some range therebetween).

The electrodes are preferably flexible in nature. In exemplaryembodiments, the conductive materials of one or more of the electrodesmay include, but are not limited to, transparent conductive polymermaterials, such as indium tin oxide (ITO), fluorine-doped tin oxide(FTO), ZnO—Ga₂O₃, ZnO—Al₂O₃, SnO₂—Sb₂O₃, and polythiophene. In addition,the electrodes may be comprised of silver or copper grids or bushbarsplated on a transparent substrate or silver nanowires or nanoparticlesdeposited on a substrate with a poly(3,4-ethylenedioxythiophene)poly(styrenesulfonate) (PEDOT:PSS) coating. Additional conductivepolymer layers may be added to improve conductivity.

In one aspect, the transparent conductive electrode may be carbon-based,for example, carbon nanotubes, carbon nanowires, or graphene, and thelike. One preferred electrode (typically for infrared) comprisesgraphene. While one or two layers of graphene is preferred, theelectrode may comprise about 1 to 20 layers of graphene (e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 layers orsome range therebetween). The graphene electrode(s) also have the effectof protecting the photoactive layer sandwiched between them fromoxidation. Therefore, environmental stability of the device can beimproved. The graphene electrode may optionally have a plurality ofplasmonic nanostructures, which may have various morphologies(spherical, rods, discs, prisms, etc.). Exemplary nanostructures includethose made of gold, silver, copper, nickel, and other transition metals,for example gold nanoparticles, silver nanoparticles, coppernanoparticles, nickel nanoparticles, and other transition metalnanoparticles. In general, any electrically conductive materials, suchas oxides and nitrides, of surface plasmonic resonance frequencies inthe visible spectrum can be made into plasmonic nanostructures for thesame purpose. In exemplary embodiments, the plasmonic particles have thesize of about 1 nm to about 300 nm (e.g., about 10, 50, 100, 150, 200,250, 300 nm, or some range therebetween).

Light Source

In some exemplary embodiments, the device of the present inventionincludes a thin light source that may comprise, for example, OLEDs orprintable LEDs (organic or inorganic). In general terms, the lightsource comprises a flexible light emitter located between two conductivelayers (i.e., electrodes) comprising an anode and a cathode, wherein theflexible light emitter emits light in response to an electric currentapplied to the anode and cathode. One typical light source uses atransparent substrate, a transparent anode, a flexible light emitter,and a reflective cathode. Light generated from the flexible lightemitter is emitted through the transparent anode and transparentsubstrate. This is commonly referred to as a bottom-emitting lightsource. Alternatively, the light source may include a substrate, areflective anode, a flexible light emitter, a transparent cathode, and atransparent encapsulating cover. Light generated from the flexible lightemitter is emitted through the transparent cathode and transparentencapsulating cover. This is commonly referred to as a top-emittinglight source. The present invention includes light sources having bothbottom-emitting and top-emitting configurations. Of course, one skilledin the art will appreciate that other types of light sources may also beused in accordance with the present invention.

As used herein, the term “transparent” generally means transparency forlight and includes both clear transparency as well as translucency.Generally, a material is considered transparent if at least about 50%,preferably about 60%, more preferably about 70%, more preferably about80% and still more preferably about 90% of the light illuminating thematerial can pass through the material. In contrast, the term “opaque”generally refers to a material in which the light is substantiallyabsorbed or reflected, e.g., at least 90% of the light is absorbed orreflected, and typically at least 95% of the light is absorbed orreflected.

The total thickness of the light source is preferably about 3 mm or less(e.g., about 3, 2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.9, 0.8,0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04,0.03, 0.02, 0.01 mm or less). The thickness of the flexible lightemitter in the light source is preferably about 2 mm or less (e.g.,about 2, 1.8, 1.6, 1.4, 1.2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2,0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 mm or less).Most preferably, the flexible light emitter is about 10 to 200 nm inthickness (e.g., about 200, 180, 160, 140, 120, 100, 90, 80, 70, 60, 50,40, 30, 20, 10 nm, or some range therebetween).

OLEDs

As noted above, the light source of the present invention may compriseOLEDs in which the flexible light emitter is a thin organic film. Asused herein, the term “organic” with respect to OLEDs encompassespolymeric materials as well as small molecule organic materials that maybe used to fabricate organic opto-electronic devices. Such materials arewell known in the art. “Small molecule” refers to any organic materialthat is not a polymer, and it will be appreciated that “small molecules”may actually be quite large. “Small molecules” may include repeat unitsin some circumstances. For example, using a long chain alkyl group as asubstituent does not remove a molecule from the “small molecule” class.“Small molecules” may also be incorporated into polymers, for example asa pendent group on a polymer backbone or as a part of the backbone.“Small molecules” may also serve as the core moiety of a dendrimer,which consists of a series of chemical shells built on the core moiety.The core moiety of a dendrimer may be a fluorescent or phosphorescentsmall molecule emitter. A dendrimer may be a “small molecule,” and it isbelieved that all dendrimers currently used in the field of OLEDs aresmall molecules. In general, a “small molecule” has a well-definedchemical formula with a single molecular weight, whereas a polymer has achemical formula and a molecular weight that may vary from molecule tomolecule.

Generally speaking, in the flexible light emitter, electrons and holesrecombine to radiate photons. The radiative photon energy emitted fromthe flexible light emitter corresponds to the energy difference betweenthe lowest unoccupied molecular orbital (LUMO) level and the highestoccupied molecular orbital (HOMO) level of the organic material. Photonsof lower energy/longer wavelength may be generated by higher-energyphotons through fluorescent or phosphorescent processes.

As described below, the flexible light emitter may optionally includeone or more of a hole injection material (HIM), a hole transportmaterial (HTM), a hole blocking material (HBM), an electron injectionmaterial (EIM), an electron transport material (ETM), an electronblocking material (EBM), and/or an exciton blocking material (ExBM).

In one aspect, the emissive electroluminescent layer may include a holeinjection material (HIM). A HIM refers to a material or unit capable offacilitating holes (i.e., positive charges) injected from an anode intoan organic layer. Typically, a HIM has a HOMO level comparable to orhigher than the work function of the anode, i.e., −5.3 eV or higher.

In another aspect, the emissive electroluminescent layer may include ahole transport material (HTM). A HTM is characterized in that it is amaterial or unit capable of transporting holes (i.e., positive charges)injected from a hole injecting material or an anode. A HTM has usuallyhigh HOMO, typically higher than −5.4 eV. In many cases, HIM can alsofunction as HTM, depending on the adjacent layer.

In another aspect, the emissive electroluminescent layer may include ahole blocking material (HBM). A HBM generally refers to a materialwhich, if deposited adjacent to an emitting layer or a hole transportinglayer in a multilayer structure, prevents the holes from flowingthrough. Usually it has a lower HOMO as compared to the HOMO level ofthe HTM in the adjacent layer. Hole-blocking layers are frequentlyinserted between the light-emitting layer and the electron-transportlayer.

In another aspect, the emissive electroluminescent layer may include anelectron injection material (EIM). An EIM generally refers to a materialcapable of facilitating electrons (i.e., negative charges) injected froma cathode into an organic layer. The EIM usually has a LUMO levelcomparable to or lower than the working function of the cathode.Typically, the EIM has a LUMO lower than −2.6 eV.

In another aspect, the emissive electroluminescent layer may include anelectron transport material (ETM). An ETM generally refers to a materialcapable of transporting electrons (i.e., negative charges) injected froman EIM or a cathode. The ETM has usually a low LUMO, typically lowerthan −2.7 eV. In many cases, an EIM can serve as an ETM as well,depending on the adjacent layer.

In another aspect, the emissive electroluminescent layer may include anelectron blocking material (EBM). An EBM generally refers to a materialwhich, if deposited adjacent to an emissive or electron transportinglayer in a multilayer structure, prevents the electron from flowingthrough. Usually it has a higher LUMO as compared to the LUMO of the ETMin the adjacent layer.

In another aspect, the emissive electroluminescent layer may include anexciton blocking material (ExBM). An ExBM generally refers to a materialwhich, if deposited adjacent to an emitting layer in a multilayerstructure, prevents the excitons from diffusing through. ExBM shouldhave either a higher triplet level or singlet level as compared to theemitting layer or other adjacent layer.

Exemplary OLED materials are described in Hammond et al., U.S. PublishedPatent Application No. 2010/0179469; Pan et al., U.S. Published PatentApplication No. 2013/0006119; Buchholz et al., PCT Published PatentApplication No. WO 2012/010238; and Adamovich et al., U.S. PublishedPatent Application No. 2007/0247061, all of which are incorporatedherein by reference.

Referring to FIG. 3A, a typical sequence of materials found in theflexible light emitter between the anode and the cathode of the OLED isHIM, HTM, emission layer, HBM, and ETM. Another typical sequence ofmaterials is HTM, emission layer, and ETM. Of course, other sequences ofmaterials are also possible and within the scope of the presentinvention. Further, the OLED may comprise one or more interlayers.

In one aspect, the flexible light emitter comprises a single layer. Theflexible light emitter may comprise, for example, a conjugated polymerwhich is luminescent, a hole-transporting polymer doped with electrontransport molecules and a luminescent material, or an inert polymerdoped with hole transporting molecules and a luminescent material. Theflexible light emitter may also comprise an amorphous film ofluminescent small organic molecules which can be doped with otherluminescent molecules.

In another aspect, the flexible light emitter may comprise one or moredifferent emissive materials in either the same emission layer or indifferent emission layers. For example, the flexible light emitter maycomprise 5, 4, 3, 2, or 1 radiation emitting materials. The variousdifferent emissive materials may be selected from the emissive materialsdescribed in the references set forth above, but any other suitableemissive material can be employed. If two emissive materials are used inone emission layer, the absorption spectrum of one of the two emissivematerials preferably overlaps with the emission spectrum of the otheremissive material. The emissive materials may be arranged in stackedlayers or side-by-side configurations. The emissive layer may comprise acontinuous region forming a single emitter or a plurality of lightemitters. The plurality of light emitters may emit light withsubstantially different wavelengths. The plurality of light emitters maybe vertically stacked within the emissive layer or they may form amixture. In some embodiments, a dopant is dispersed within an organichost matrix. In one embodiment, a layer of quantum dots is sandwichedbetween two organic thin films.

In another aspect, the flexible light emitter may comprise a pluralityof layers sharing a common anode and/or cathode. In this case,individual layers are stacked one on top of another. The stackedconfiguration may generally include intermediate electrodes disposedbetween adjacent layers such that successive layers share anintermediate electrode, i.e., a top electrode of one layer is the bottomelectrode of another in the stack. The stacked layers may be formed ofdifferent materials, and therefore, different emissions spectra.

The OLEDs may produce light in the visible range (380 to 700 nm), theultraviolet range (UVA: 315 to 400 nm; UVB: 280 to 315 nm; UVC: 100-280nm), near infrared light (700 to 1500 nm) and/or far infrared light(about 1500 to 11,000 nm). Visible light corresponds to a wavelengthrange of approximately 380 to 700 nm and are usually described as acolor range of violet through red. The human eye is not capable ofseeing radiation with wavelengths outside this visible spectrum such asin the ultraviolet or infrared range. The visible spectrum from shortestto longest wavelength is generally described as violet to deep blue(approximately 400 to 450 nm), blue (approximately 450 to 490 nm), green(approximately 490 to 560 nm), yellow (approximately 560 to 590 nm),orange (approximately 590 to 630 nm), and red (approximately 630 to 700nm). Ultraviolet radiation has a shorter wavelength than the visibleviolet light and infrared radiation has a longer wavelength than visiblered light. The emission spectrum may be one selected from a NIR, UV,white, a red, a green, a blue, a yellow, an orange, a cyan, or a magentaspectrum or a combination thereof. Selection of wavelengths fortherapeutic and/or cosmetic purposes may be made by selecting theappropriate materials and layers so that the same device may providemultiple or combined wavelengths. By appropriately mixing differentmaterials and layers, the output spectrum may also be visuallysubstantially white. The broadband spectra of individual layers may bemixed to form an output spectrum which may be very close to naturallywhite light to human eyes or as needed for the therapeutic and/orcosmetic effect.

There are multiple methods of producing white light using emissivelayers in the device of the present invention. One method is to useindividual emissive layers that emit visible light in the red range, thegreen range, and the blue range. The emissive layers may be in a singlelayer or in a layered structure. Another method involves the use of aphosphor material capable of converting monochromatic light from blue orUV to broad-spectrum white light or by converting just a portion of theblue light with a yellow emitting phosphor material.

In one aspect, the device emits a relatively broad band spectrum suchthat the full width at half maximum (FWHM) of the individual spectrummay be larger than 50 nm, 100 nm, 150 nm, or even larger than 200 nm. Inanother aspect, the device may produce a narrow band spectrum with aFWHM less than about 50 nm. This may be advantageous in certainphototherapy applications where the tissue or photosensitizingmedication responds to a narrow wavelength range.

The flexible light emitter may be substantially transparent. When mostlytransparent layers are used, a plurality of emissive layers may bevertically stacked without substantially blocking light emission fromindividual layers. The flexible light emitter may comprise a single ormultiple layers, for example, a combination of p- and n-type materials.The p- and n-type materials may be bonded to each other in the layer.The bonding may be ionic or covalent bonding, for example. The multiplelayers of the flexible light emitter may form heterostructurestherebetween.

Printable LEDs

As noted above, the light source of the present invention may compriseprintable LEDs (organic or inorganic). There are several known methodsfor printing such LEDs, as described below.

In one method, the light source comprises a plurality of individual LEDssuspended and dispersed in a liquid or gel comprising one or moresolvents and a viscosity modifier so as to form a diode ink that iscapable of being printed on a flexible substrate (e.g., through screenprinting, flexographic printing and the like). In one aspect, theaverage surface area concentration of LEDs is from about 25 to 50,000LEDs per square centimeter. In general, each LED includes a lightemitting region, a first metal terminal located on a first side of thelight emitting region, and a second metal terminal located on a secondside of the light emitting region. The first and second metal terminalsof each LED may be electrically coupled to conductive layers (i.e.,electrodes) to enable the light emitting region to emit light whenenergized.

An exemplary light source is shown generally in FIG. 3B, wherein onlyfive LEDs are provided in order to simplify the description. As can beseen, this light source includes a plurality of conductors 80 a-80 edeposited on a flexible substrate 82. A plurality of LEDs 84 a-84 e aredeposited on the conductors 80 a-80 e such that the first metalterminals of the LEDs 84 a-84 e are electrically coupled to theconductors 80 a-80 e. One skilled in the art will appreciate that theLEDs 84 a-84 e may be formed of various shapes. Preferably, the LEDs 84a-84 e settle into a position over conductors 80 a-80 e such that theymaintain their polarity based on the shape of the LEDs. Next, aplurality of dielectric layers 86 a-86 e are deposited over the LEDs 84a-84 e and the conductors 80 a-80 e, as shown. Another conductor 88 isthen deposited over the LEDs 84 a-84 e and dielectric layers 86 a-86 esuch that the second metal terminals of the LEDs 84 a-84 e are coupledto the conductor 88. One skilled in the art will appreciate that thesubstrate 82 and conductors 80 a-80 e may be transparent so that lightis emitted from the bottom of the device and/or conductor 82 may betransparent so that light is emitted from the top of the device.

Various configurations of printable LEDs that may be manufactured inaccordance with the above method are described in Lowenthal et al., U.S.Pat. No. 8,415,879, which is incorporated herein by reference.

In another method, the light source comprises LEDs that are createdthrough a printing process. In this method, a substrate is provided thatincludes a plurality of spaced-apart channels. A plurality of firstconductors are formed on the substrate such that each first conductor ispositioned in one of the channels. Next, a plurality of substantiallyspherical substrate particles are coupled to the first conductors and,then the substantially spherical substrate particles are converted intoa plurality of substantially spherical diodes. The substantiallyspherical diodes may comprise, for example, semiconductor LEDs, organicLEDs encapsulated organic LEDs, or polymer LEDs. A plurality of secondconductors are then formed on the substantially spherical diodes.Finally, a plurality of substantially spherical lenses suspended in apolymer (wherein the lenses and suspending polymer have differentindices of refraction) are deposited over the substantially sphericaldiodes and the second conductors. Thus, in this method, the LED's arebuilt up on the substrate as opposed to being mounted on the substrate.Various configurations of printable LEDs that may be manufactured inaccordance with the above method are described in Ray et al., U.S. Pat.No. 8,384,630, which is incorporated herein by reference.

Micro-Lens Array

In the present invention, the device may optionally include a lightdispersion layer, such as a micro-lens array. It has been found that oneof the key factors that limits the efficiency of OLED devices is theinefficiency in extracting the photons generated by the electron-holerecombination out of the OLED devices. Due to the high optical indicesof the organic materials used, most of the photons generated by therecombination process are actually trapped in the devices due to totalinternal reflection. These trapped photons never leave the OLED devicesand make no contribution to the light output from these devices. Inorder to improve the extraction or out-coupling of light from OLEDs, thedevice may include an internal scattering layer of high index particlessuch as TiOx in a transparent photoresist or a micro-lens array (MLA)layer. Exemplary MLAs and methods for forming the same are described inGardner et al., U.S. Published Patent Application No. 2004/01217702;Chari et al. U.S. Pat. No. 7,777,416; Xu et al., U.S. Pat. No.8,373,341; Yamae et al., High-Efficiency White OLEDs with Built-upOutcoupling Substrate, SID Symposium Digest of Technical Papers, 43 694(2012); and Komoda et al., High Efficiency Light OLEDS for Lighting, J.Photopolymer Science and Technology, Vol. 25, No. 3 321-326 (2012).

Ultrasonic Transducer

In some exemplary embodiment, the device of the present inventioncomprises an ultrasonic transducer for producing ultrasound. In oneaspect, the device produces low frequency ultrasound. In another aspect,the device produces high frequency ultrasound. In still another aspect,the device produces both low frequency ultrasound and high frequencyultrasound (i.e., a dual frequency ultrasound device) and may haveeither a unimorph design or a bimorph design, as discussed below. Thelow and high frequency ultrasound can be applied simultaneously,sequentially or separately, e.g., sequentially as several alternatingsingle applications of low and high frequency ultrasound or separatelywhere a series of applications of low frequency ultrasound is alternatedwith a series of applications of high frequency ultrasound.

“Ultrasound” as used herein includes near ultrasound and generallyrefers to sound at a frequency of greater than about 2 kHz up to about20 MHz or more (e.g., 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000,6000, 7000, 8000, 9000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000,16,000, 17,000, 18,000, 19,000, 20,000 kHz, or some range therebetween).As used herein, “low frequency ultrasound” includes near ultrasound andgenerally has a frequency in the range of about 2 kHz to 500 kHz (e.g.,about 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220,240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500 kHzor some range therebetween). Preferred low frequency ultrasound rangesare about 2 kHz to 200 kHz, 15 kHz to 150 KHz, 15 kHz to 100 kHz, 35 kHzto 100 kHz, and more preferably about 50 kHz to 100 kHz. As used herein,“high frequency ultrasound” includes ultrasound generally having afrequency in the range of about 500 kHz to 20 MHz or more (e.g., about500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000,9000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000,18,000, 19,000, 20,000 kHz or some range therebetween). Preferred highfrequency ultrasound ranges are about 0.5 to 15 MHz, 0.5 to 10 MHz, 0.5MHz to 5 MHz, 0.5 MHz to 3.5 MHz, 1 MHz to 5 MHz, 1 MHz to 3.5 MHz, 1.5MHz to 3.5 MHz, and 1 to 3 MHz.

In one aspect, the device produces low frequency ultrasound (preferablyabout 2 kHz to 200 kHz, even more preferably about 35 kHz to 100 kHz,and still more preferably about 50 to 100 kHz) and high frequencyultrasound (preferably about 0.5 MHz to 5 MHz, more preferably about 0.5MHz to 3.5 MHz, even more preferably about 1 to 3 MHz). The high or lowfrequency ultrasound may be provided in continuous or pulsed modesmodulated at frequencies of 0.1 Hz to 5 kHz, preferably in the range ofabout 10 to 1000 Hz (e.g., 10, 50, 100, 200, 300, 400, 500, 600, 700,800, 900, 1000 Hz or some range therebetween at various duty factors,preferably in the range of 5-50% (e.g., about 5, 10, 15, 20, 25, 30, 35,40, 45, 50% or some range therebetween), typically in the range of 10%to 20%.

In the present invention, the ultrasonic transducer in its simplest formcomprises a thin, flexible ultrasound emitter (e.g., a piezoelectriccoating (film or paint) or piezoceramic material) sandwiched between apair of thin conductive electrodes. It will be appreciated that theelectrodes for the flexible ultrasound emitter need not be transparent.Further, it will be appreciated that, in some embodiments, the cathodeof the light source may also function as the cathode of the ultrasonictransducer. The ultrasonic transducer may operate at a variety offrequencies, including low and/or high frequencies.

The thickness of the flexible ultrasound emitter is a function of thefrequency of the sound waves. Preferred thicknesses for the flexibleultrasound emitter (e.g., a piezoelectric coating (film or paint)) areabout 50 to 200 μm (e.g., about 50, 60, 70, 80, 90, 100, 110, 120, 130,140, 150, 160, 170, 180, 190, 200 μm, or some range therebetween). Inother embodiments, the flexible ultrasound emitter (e.g., a piezoceramicmaterial) may have a thickness of about 3 mm or less (e.g., about 3,2.8, 2.6, 2.4, 2.2, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.9, 0.8, 0.7, 0.6, 0.5,0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01mm or less).

In one embodiment, the device generates low frequency ultrasound. Thedevice may generate low frequency ultrasound in at least three ways.

First, the device may include an ultrasonic transducer capable ofgenerating ultrasound having a frequency of about 2 kHz to 500 kHz,preferably about 2 kHz to 200 kHz.

Second, the device may include an ultrasonic transducer capable ofgenerating ultrasound at a frequency of about 100 kHz to 20 MHz (e.g.,about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000,2500, 3000, 3500, 4500, 5000, 6000, 7000, 8000, 9000, 10,000, 11,000,12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000kHz or some range therebetween) modulated at a frequency of about 2 kHzto 500 kHz, preferably about 2 kHz to 200 kHz. That is, the ultrasoundsignal is “on/off” at a frequency of 2 kHz to 500 kHz, preferably about20 kHz to 200 kHz.

Third, the device may include an ultrasonic transducer capable ofgenerating vibrational energy at a frequency of about 10 Hz to 1000 Hz(e.g., about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300,400, 500, 600, 700, 800, 900, 1000 Hz or some range therebetween)modulated at a frequency of about 2 kHz to 500 kHz, preferably about 2kHz to 200 kHz. That is, the vibrational energy produced by thetransducer is “on/off” at a frequency of 2 kHz to 500 kHz, preferablyabout 2 kHz to 200 kHz. In one embodiment, the device produces vibrationof about 10 Hz to 1000 Hz, preferably about 10 Hz to 100 Hz, morepreferably about 10 Hz to 50 Hz, and most preferably about 15 Hz to 30Hz, which is felt on the transducer surface, and can be tuned usingpulse modulated currents to optimize higher frequency harmonics in therange of about 15 kHz to 100 kHz, more preferably about 15 kHz to 50kHz, and most preferably about 15 kHz to 35 kHz.

The intensity of the low frequency ultrasound is preferably in the rangeof between about 0 and 3.0 W/cm² (e.g., about 5, 50, 100, 150, 200, 250,300, 350, 400, 450, 500, 1000, 1500, 2000, 2500, 3000 mW/cm2 or somerange therebetween), more typically between about 5 mW/cm² and 200mW/cm². Exposures to the treatment site are typically for a period ofbetween about 1 and 15 minutes (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 minutes), but may be shorter or longer and/orpulsed. Other ultrasonic transducer parameters including, but notlimited to, amplitude, duty cycle, distance from the treatment site, andapplication time may be varied to achieve sufficient enhancement oftransdermal transport. The pressure amplitude may be varied from aboveabout 0 to 50 kPa. The duty cycle can vary from between about 1% and100%. The displacement may vary from about 25 picometers to severalhundred nanometers.

The ultrasonic transducer may be made of any suitable ultrasoundtransducer material, such as a flexible piezoelectric coating (film orpaint), a ceramic transducer, or a polymer block transducer. Thetransducer may be comprised of quartz, polyvinylidene fluoride (PVDF),ceramic including PZT and screen printed ceramic, magnetostrictive, orcomposite material including molded ceramic and benders. For example,the piezoelectric material may be selected from the group consisting ofPZT, PVDF, lead zirconate titanate Pb(Zr,Ti)O3, lead metaniobatePb(Nb2O6), modified lead titanate PbTi3, (Pb,Ca)TiO3, (Pb,Sm)TiO3,barium titanate BaTiO3, PMN-PT(1−x)Pb(Mg⅓,Nb⅔)O3−xPbTiO3, PZN-PT/BTPb(ZN⅓,Nb⅔)O3−x Pb TiO3-BaTiO3,(1−x)Pb(ZN⅓,Nb⅔)O3−x(yPbTiO3-(1−y)PbZrO3).

In a preferred aspect, the transducer is comprised of a flexiblepiezoelectric coating (film or paint), such as PVDF or a co-polymerthereof. It will be appreciated to those skilled in the art that recentdevelopments in flexible piezoelectric coatings, such as the PiezoPaint™material available from Meggitt PLC, provide a piezoelectric materialthat can be applied on a variety of substrates. For example, thePiezoPaint™ PP-50B material is flexible, printable (e.g., usingscreen-printing, pad-printing or stencil printing techniques), exhibitsrelatively high sensitivity (d₃₃ coefficient up to 45 pC/N), and may beprocessed at extremely low temperatures (less than 150° C.). Of course,other flexible piezoelectric coatings may also be used in the device ofthe present invention.

As noted above, the device may generate both low frequency ultrasoundand high frequency ultrasound (i.e., a dual frequency ultrasound device)and may have either a unimorph design or a bimorph design.

With a unimorph design, a single ultrasound emitter is used to deliverlow frequency ultrasound in the range of 2 kHz to 500 kHz and highfrequency ultrasound in the range of 500 kHz to 20 MHz. In one aspect,the ultrasound emitter comprises a flexible piezoelectric coating (e.g.,PiezoPaint™ material by Meggitt PLC) that is able to operate at both lowand high frequencies (i.e., a broadband device).

In one embodiment, the ultrasound emitter is bonded to an elasticsubstrate (e.g., a metal substrate) in such a manner as to generate bothlow and high frequency ultrasound. In this case, the device is designedto use the lateral resonance of the ultrasound emitter in combinationwith the substrate so as to optimize low frequency resonance and providea low frequency mechanical bending resonance mode, while also enablingthe thickness resonance mode to provide high frequency operation. Assuch, the ultrasound emitter has a low frequency mechanical bendingresonance mode when the ultrasound emitter is excited, in use, by avoltage which includes a low frequency oscillating component, and alsohas a relatively high frequency thickness resonance mode when theultrasound emitter is excited, in use, by a voltage which includes arelatively high frequency oscillating component. An example of such adevice is described in Galluzzo et al., U.S. Published PatentApplication No. 2012/0267986, which is incorporated by reference in itsentirety. In this embodiment, the substrate may function as the cathode(or anode) for the ultrasonic transducer, as well as a common cathodefor the light source.

Alternatively, the ultrasound emitter operates in a conventional lateralresonance mode to deliver lower frequency ultrasound and a thicknessresonance mode to deliver higher frequency ultrasound. In this case, theultrasound emitter is not bonded to a substrate as described above. Sucha design is not preferred insofar as the range of frequencies producedbetween the lateral resonance mode and the thickness resonance mode arelimited to a ratio of about 6:1. As such, the device would not, forexample, be able to provide low frequency ultrasound at 50 kHz and highfrequency ultrasound at 3 MHz. With that said, such an ultrasoundemitter could be used as either a low frequency transducer or a highfrequency transducer whereby the additional operating frequency providesa therapeutic effect.

With a bimorph design, two different ultrasound emitters are used todeliver low frequency ultrasound in the range of 2 kHz to 500 kHz andhigh frequency ultrasound in the range of 500 kHz to 20 MHz. In apreferred embodiment, each of the low and high frequency ultrasoundemitters comprises a flexible piezoelectric coating (e.g., PiezoPaint™material by Meggitt PLC), wherein one ultrasound emitter is driven at alow frequency and the other ultrasound emitter is driven at a highfrequency. These materials are able to deliver ultrasound in a widerange of frequencies, e.g., low frequency ultrasound at 50 kHz and highfrequency ultrasound at 3 MHz. An example of such a device is describedin Luebecke, U.S. Published Patent Application No. 2008/0051580, whichis incorporated by reference in its entirety.

Low frequency ultrasound is believed to be useful to facilitate deliveryof molecules through the skin (a process termed “sonophoresis”). The lowfrequency ultrasonic energy provides cavitational effects in the skin,which improves drug delivery into and through the skin. In particular,the application of low frequency ultrasound (e.g., about 2 kHz to 200kHz) dramatically enhances transdermal transport of drugs. Cavitationmay cause disordering of the stratum corneum lipids. In addition,oscillations of cavitation bubbles may result in significant waterpenetration into the disordered lipid regions. This may cause theformation of aqueous channels through the intercellular lipids of thestratum corneum. This allows permeants to transport across thedisordered lipid domains, then across keratinocytes and the entirestratum corneum. This transport pathway may result in an enhancedtransdermal transport as compared to passive transport because thediffusion coefficients of permeants through water, which is likely toprimarily occupy the channels generated by ultrasound, are up to1000-fold higher than those through the ordered lipid bilayers, and thetransport path length of these aqueous channels may be much shorter(e.g., by a factor of up to about 25) than that through the tortuousintercellular lipids in the case of passive transport.

High frequency ultrasound has a lesser sonophoretic effect than lowfrequency, although it is capable of sonophoresing small molecules(typically less than about 500 daltons). However, high frequencyultrasound has many other effects beneficial to the skin in that itstimulates fibroblast proliferation, stimulates collagen and otherextracellular matrix (ECM) component formation (e.g., fibrillin),stimulates blood supply, renews the elastic quality of ECM which stiffenwith age, stimulates the expression of Heat Shock Proteins(HSPs—intracellular molecular chaperones) in fibroblasts (dermis) andkeratinocytes (epidermis) through thermal and mechanical stimulation.

Other ultrasound parameters that may be readily determined by thoseskilled in the art include, but are not limited to, amplitude, dutycycle, distance from the skin, coupling agent composition, andapplication time, which may be varied to achieve sufficient enhancementof transdermal transport and therapeutic dose.

Matching Layer

The device of the present invention may optionally include an acousticimpedance matching layer. The matching layer is typically locatedbetween the skin-facing surface of the device and the ultrasonictransducer. Most preferably, the matching layer is transparent, flexibleand/or conformable in nature. Ideally the material is latex-free,non-toxic, non-allergenic material, which is resistant to UV, sunlightand most infection control products.

It will also be appreciated that the device may include multiplematching layers, as desired. When an acoustic wave encounters a boundarybetween two layers having a relatively large variance in theirrespective acoustic impedances, the acoustic wave is reflected at theboundary. Using a plurality of matching layers enables the acousticimpedance of each layer to be varied gradually to minimize reflections.It will also be appreciated that the larger the difference in theacoustic impedances of the therapeutic and/or cosmetic composition andthe transducer, more matching layers may be employed to minimizereflections.

In one embodiment, the acoustic impedance of the therapeutic and/orcosmetic composition is matched closely enough to the acoustic impedanceof the skin boundary, such that reflections at the skin layer boundaryare minimized. As noted above, it is desirable to have some of theacoustic energy pass through the skin layer boundary into the tissue toprovide a cavitation or therapeutic effect. The matching layer(s) thusdirect the ultrasound acoustic energy from the transducer to thetherapeutic and/or cosmetic composition, and the therapeutic and/orcosmetic composition may also act as a matching layer to direct some ofthe ultrasound into the upper layers of the dermal or epidermal tissue.

In exemplary embodiments, the matching layer may be comprised of asilicon-based material, rubber, thermoplastic elastomers (TTP), or otherpolymeric material, such as polyester, polyethylene terephthalate (PET),polyethylene naphthalate (PEN), polycarbonate, polystyrene, polyacryl,polyether sulfone (PES), etc. Transparent matching layers may include,for example, polyethylene, ethylene-vinyl acetate copolymers, polyimide(PI), polyetherimide (PEI), ethylene-vinyl alcohol copolymers,polypropylene, polystyrene, polymethyl methacrylate, PVC, polyvinylalcohol, polyvinylbutyral, polyether ether ketone, polysulfone,polyether sulfone, as well as fluoropolymers, such as, fluorinatedethylene-propylene (FEP), tetrafluoroethylene-perfluoroalkyl vinyl ethercopolymers, polyvinyl fluoride, tetrafluoroethylene-ethylene copolymers,tetrafluoroethylene-hexafluoropropylene copolymers,polychlorotrifluoroethylene, polyvinylidene fluoride, polyester,polycarbonate, polyurethanes, polyimide, and thermosets such as epoxies.Because the acoustic impedance of many polymeric materials is less thanthe preferred range, it may be necessary to increase the acousticimpedance by incorporating a filler such as PZT, tungsten, silica glass,titanium, tungsten carbide and glass powder. Typically, a particle sizeof 0.5 to 5 microns is used, and a filler in the range of 5 to 30% byvolume is used although other percentages may be appropriate based onthe material and particle size.

In another exemplary embodiment, the matching layer is a polyester film,such as Mylar. In another aspect, the substrate serves as the matchinglayer and comprises a polyetheretherketone film commercially availablefrom Victrex under the name APTIV. In still another aspect, the matchinglayer is a thin film sold under the name Flexent by Konica Minolta orflexible glass such as Willow Glass by Dow Corning.

Transparent Heater Layer

The device of the present invention may also include an optional heaterlayer, which is preferably transparent, flexible and/or conformable. Inone embodiment, the flexible transparent heater layer is formed adjacentthe matching layer(s). Alternatively, the flexible transparent heaterlayer may be a part of the matching layer(s). For example, graphene maybe incorporated into a polyethylene terephthalate (PET) film which isimbedded in or bonded to the matching layer to form a flexibletransparent heater layer. The heater layer provides an even heatingacross the surface due to the printing or deposition of the heaterlayer. This is of importance in reducing hot spots and providing evenheating over the tissue surface. Exemplary materials and methods forforming the flexible transparent heater layer are described in Kang etal., High-performance graphene-based transparent flexible heaters, NanoLett 11 (12):5154-8 (2011); Sui et al., Flexible and TransparentElectrothermal Film Heaters Based on Graphene Materials, Small, Vol. 7,Issue 22, 3186-3192 (Nov. 18, 2011). The flexible transparent heaterlayer may be driven by AC, DC, or pulsed DC. Typically, low voltages andcurrents are needed to increase the tissue temperature from about 1 to4° C. using resistive heating elements.

In one aspect, the device of the present invention is well adapted toprovide light energy, ultrasound, and mild heating of about 1 to 2° C.(e.g., via light energy from the light source, ultrasound from theultrasonic transducer, and heat from the flexible transparent heaterlayer, or combinations thereof). It is theorized that low frequencyultrasound causes cavitational effects which assist in the movement oftherapeutic and/or cosmetic agents, such as those containing ascorbicacid, through the skin. Among other things, the light energy triggersthe collagen regeneration and production by activation of fibroblasts.Heating the skin further assists in increasing transdermal permeabilityand increases microvascular perfusion, providing nutrients to the dermaland epidermal layers of the skin and underlying tissue.

In another aspect, the device of the present invention is well adaptedto provide light energy, ultrasound, and mild heating of about 2 to 4°C. (e.g., via light energy from the light source, ultrasound from theultrasonic transducer, and heat from the flexible transparent heaterlayer, or combinations thereof). It is theorized that low frequencyultrasound causes cavitational effects which assist in the movement oftherapeutic and/or cosmetic agents, such as those containing ascorbicacid, through the skin. Among other things, the light energy triggersthe collagen regeneration and production by activation of fibroblasts.The heating increases blood flow and assists in collagen remodeling.Heating of collagenous fibers also allows plastic deformation usingheat-and-stretch to reform collagen and flatten out areas of tissueirregularities such as scar tissue, wrinkles and dermal lesions.

Electrical Stimulation Layer

The device of the present invention may include an optional electricalstimulation layer. The electrical stimulation layer is well suited toiontophoretically deliver a charged therapeutic and/or cosmetic agent tothe skin, decrease muscle spasms or muscle hypertonicity, or improvemuscle tone in case of muscle hypotonicity.

During iontophoresis, the current (which is typically DC or pulsed DC)is used to cause the therapeutic or cosmetic agent ions to move acrossthe surface of the skin and diffuse into underlying tissue. To create aniontophoretic circuit, the positive and negative poles of thecontrollable waveform generator are electrically connected to positiveand negative electrodes, respectively, applied to the skin of thepatient. To iontophoretically deliver a positively charged medicament,the composition containing the medicament is coupled to the electricalstimulation layer in the device which is a positive electrode. Anegative return electrode is applied to the surface of the skin at aseparate location. On the other hand, to iontophoretically deliver anegatively charged medicament, the composition containing the medicamentis coupled to an electrical stimulation layer in the device which is anegative electrode. A positive return electrode is applied to thesurface of the skin at a separate location. Electrical current flowsfrom the generator to the positive electrode and through the patient'sskin to the negative electrode. The electromotive differential betweenthe positive electrode and the negative electrode induces the negativepolarity medicament to move as negative ions through the surface of thepatient's skin in the direction of the positive electrode.

In another aspect, the return electrode is incorporated into the deviceitself. For example, one or more return electrodes may be positioned atthe periphery of the surface of the device that is in contact with theskin, for example, adjacent to the matching layer of the device.

In one aspect, the electrical current is a DC current. In anotheraspect, the electrical current applied to the electrical stimulationlayer comprises a DC current superimposed with either an AC current or apulsed DC current. Preferably, the current ranges from about 1 to 10 mA(e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mA, or some rangetherebetween) with about 2 to 4 mA being most preferred. The voltage istypically 100 V or less (e.g., about 100, 90, 80, 70, 60, 50 or 40 V orless). Typically, the treatment time is about 10 to 20 minutes such thatthe dosage per treatment time is about 40 to 80 mA*min (e.g., about 40,50, 60, 70 or 80 mA*min).

In this embodiment, the therapeutic and/or cosmetic composition mayinclude one or more therapeutic and/or cosmetic agents, such as thosedescribed herein. In one aspect, the therapeutic and/or cosmeticcomposition is incorporated into a gel or gel pad (such as a hydrogel orhydrogel gel pad) which is applied to the surface of the skin. Thetherapeutic and/or cosmetic composition may be incorporated into amembrane containing apparatus which controls the transport of moleculesthrough the membrane with the exposure of ultrasound generated by thedevice, such as in Kost et al., U.S. Pat. No. 7,480,212. The conductivegel or gel pad may include, for example, a metal such as aluminum,carbon film or carbon film coated with a conductor such as silver, orsilver chloride to reduce the potential for burns of the superficialtissue of the skin from the application of current. The therapeuticand/or cosmetic agent may comprise any conductive ionic molecule orcompound that can be transdermally administered to a patient with aniontophoretic delivery system. Examples of common positive active agentsinclude amine containing drugs, such as bupivacaine hydrochloride andlidocaine. Examples of common negative active agents include acidicdrugs, such as ascorbic acid, acetic acid, salicylic acid, etc. Ofcourse, the delivery of other active agents are also within the scope ofthe present invention.

The inclusion of an electrical stimulation layer in the device of thepresent invention permits electrical stimulation to be applied to thepatient's skin. In one aspect, the device is capable of providingelectroanethesia to the patient. In such a case, the devices are wellsuited for use in conjunction with a cosmetic procedure, such as laserresurfacing, fractal laser applications, plash phototherapy, ultrasound,light and surgeries using scalpels or other cutting or remodelingdevices. Of course, other types of cosmetic procedures are also withinthe scope of the invention.

It will also be appreciated that the flexible transparent conductivelayer (such as one containing graphene) may serve as the electricalstimulation layer. The graphene may be electrically coupled to a returnelectrode. Further, such a device can be used with a therapeutic and/orcosmetic composition which is conductive and typically ionic in nature.A return electrode is provided from the device on the body of the personundergoing treatment. Typically, a pulsed monophasic or DC current ofthe appropriate polarity is used to provide an iontophoretic effect toenhance ionic transport of the therapeutic and/or cosmetic compositionthrough the skin. The composition also serves as an impedance matchinglayer between the conductive matching layer (containing the graphene)and the skin layer. Additional materials such as silver or silverchloride nanoparticles may also be coated on the electrode surface orincluded in the composition and/or hydrogel layer to buffer theiontophoretic composition. As an additional feature of the device of thepresent invention, a pulsed DC or AC current may be used in patternsthat reduce muscle hypertonicity or reduce muscle disuse atrophy. Thesecurrents may be based on EMG firing patterns of agonist and antagonistmuscles or sequences of stimulation which act in a similar way tovoluntary exercise in the building of muscle strength, power andendurance. The on and off times, ramps, duty factors, waveforms, currentlevels and impedance requirements are well known in the art and are wellestablished in this regard.

Ultrasonic Reflective Layer or Ultrasonic Absorptive Backing Layer

The device of the present invention may optionally include an ultrasonicreflective layer or ultrasonic absorptive backing layer. The ultrasonicreflective layer or ultrasonic absorptive backing layer is locatedbetween the surface of the device facing away from the skin and theultrasonic transducer. The ultrasonic reflective layer is designed toprevent undesirable backward leakage of ultrasonic waves away from thepatient. The ultrasonic reflective layer is typically a half-wavelengthor quarter-wavelength reflector, which is made of high acousticimpedance materials, such as copper, other metals or ceramics. Theultrasonic reflective layer is preferably configured such that the phaserelationship of the ultrasound is summative.

With some devices, it may not be desirable to have the ultrasoundreflect back to the patient. Further, the reflection may provide acanceling phase which may reduce output. Thus, the device may include anultrasonic absorptive backing layer. The absorptive backing layer isusually made of a material with acoustic impedance close to thepiezoelectric resonator and having a very high damping coefficient.Because the acoustic impedance of the backing layer material is similarto that of the piezoelectric material, most of the backward transmittedwave quickly attenuates and become heat, and only a very small portionmay bounce back. Commonly used backing layer materials includetungsten-loaded epoxy, pyrolytic, brass and carbon, etc. Although stillplaying the role of damping the backward waves, a proper matching layercan increase the energy transmitting efficiency from the front end sothat less energy will be reflected. If the matching layer is optimized,the backing layer may not be needed. In fact, air backing designs may beused as is known in the art.

Encapsulation Layer or Other Covering

The device of the present invention may optionally include one or moreencapsulation or barrier layers that isolate the light source and/orultrasonic emitter (or other layers) from an ambient environment. Theencapsulation or barrier layer is preferably substantially impermeableto moisture and oxygen. In general, the moisture and oxygen sensitivecomponents should be enclosed by materials having gas permeationproperties. The barrier preferably achieves low water vapor permeationrates of 10⁻⁴ g/m²/day or less, 10⁻⁵ g/m²/day or less, and even morepreferably about 10⁻⁶ g/m²/day or less.

The encapsulation or barrier layer may be glass or a plastic, forexample. Exemplary materials include a polyetheretherketone filmcommercially available from Victrex under the name APTIV. In stillanother aspect, the substrate is a thin film sold under the name Flexentby Konica Minolta or flexible glass such as Willow Glass by Dow Corning.Ideally substrates in direct contact with organic layers will haveexceptional barrier capabilities that withstand heat, offer flexibility,have sustained reliability and can be mass produced.

The device may be further covered with a transparent or semi-transparentcovering. The covering may provide comfort for a patient using thedevice particularly if the patient is lying on the device. The coveringmay provide protection to the device, keeping dirt and fluid off of thedevice and providing a cushion to protect the device from impact.

Arrays

In another aspect, the present invention is directed to a light and/orultrasonic system comprising a plurality of the devices (each containinga light source and/or ultrasonic transducer as provided herein) arrangedin an array and held in proximity to each other by a flexible,preferably transparent, material. The flexible material may beacoustically matched to the ultrasonic transducers of the devices in thearray. The flexible material typically comprises a polymeric materialselected from thermoplastics, thermosets, rubbers, or mixtures thereof.The flexible acoustically matched material will ordinarily be formedfrom a polymeric material, and optionally, a filler. The polymericmaterial should have good compatibility with the components of thetransducer, biocompatibility, and flexibility. Suitable polymericmaterials include thermoplastics such as high density polyethylenes,polymethyl methacrylates, polypropylenes, polybutylene terephthalates,polycarbonates, polyurethanes such as CA 118 and CA 128 available fromMorton Chemical and estane polyester, and the like; thermosets such asepoxies, including Spurr epoxy and Stycast 80, Stycast 1365-65 and thelike; and rubbers such as silicone rubbers such as dispersion 236available from Dow Corning and RTV-141 available from Rhone-Poulenc,Inc. and the like. The flexible material may also comprise Kapton®polyimide film, which has stable mechanical, physical and thermalproperties as well as high tensile strength and folding endurancesuitable for use when wrapped around the human anatomy. If desired, theacoustic impedance of the polymeric materials may be increased by theincorporation of one or more fillers. Suitable fillers include PZT,tungsten, alumina, silica glass, tungsten carbide, titanium, glasspowder and the like with glass powder being preferred. The size of thefiller particles should be in the range of about 0.1 to about 50 micronsand preferably from about 0.5 to about 5 microns. The amount of filleremployed will be that amount necessary to impart the desired acousticimpedance. Normally, from about 2 to about 50 percent filler by volumeand preferably from about 5 to about 30 percent filler by volume isemployed. A preferred polymeric material is silicone rubber.

The devices within the array may be the same or different, for examplein terms of the shape, size, light output and/or ultrasonic output. Thedevices within the array may produce ultrasound of differentfrequencies, power densities, duty factors and modulation frequencies.Such parameters of the devices may be pre-programmed into an electroniccontrol module. Each of the devices within the array may beindependently controlled by the control module. Each light source and/orultrasonic transducer within each of the devices of the array may beindependently controlled by the control module such that each device iscapable of delivering light and ultrasound simultaneously orsequentially in pulsed or continuous modes.

The array can be programmed to deliver a desired sequence of lightand/or ultrasound frequencies, in pulsed or continuous mode, in setpatterns, thereby avoiding problems of over or under exposure of theskin to the light and/or ultrasound, which can cause overheating of theskin. The array is controllable such that light and/or ultrasoundfrequencies are capable of being driven so that the light and/orultrasound field moves across the array in a preset, pseudorandom orrandom pattern and at a preset, pseudorandom, or random speed, forexample 2-3 seconds from left to right across the full width (e.g., 5-10cm) of the array then 2-3 seconds back again, i.e., 4-6 seconds cycletime; or into the centre of the array and then out again, especially ifthe array has a circular shaped geometry. The pattern can be variedwithin the same treatment session, e.g., left to right then up and down.The pattern may be random or pseudorandom to mimic a manual applicationof a single or multiple head transducer that is moved by a clinicianover a treatment surface. The pattern may change based on sensor inputdependent on the treatment being performed. For example, if an areabecomes too hot, the pattern may be altered to decrease the time orexposure over that tissue area.

The use of an array such that the light and ultrasound field movesacross the array in a preset pattern and at a preset speed offersseveral advantages. A major cause of potential damage to the skin isoverheating in the superficial skin where a high density of collagenoustissue is located—this area rapidly absorbs ultrasound and may overheatif the light and ultrasound field is not continuously moved. Also, thepreset speed of the light and ultrasound field should preferablycorrespond to the typical movement of a single light/transducer assemblyover a typical treatment site of two times the dimensional surface areaof the device. This enables a non-attended safe treatment without theneed for constant movement of the device. Further, the movement of thelight and ultrasound field will reduce and possibly prevent unstablecavitation from forming in the field that can lead to thermal damage inthe tissue.

Compositions Containing Active Therapeutic and/or Cosmetic Agents

In one aspect, the device of the present invention may be used inconjunction with a therapeutic and/or cosmetic composition comprising atherapeutic and/or cosmetic agent to be applied to the skin, includinglotions, gels, creams, ointments, foams, roll-on formulations, mousses,aerosol and non-aerosol sprays. The composition ispharmaceutically-acceptable such that the ingredients are suitable foruse in contact with the barrier membrane (e.g., the skin or mucosa)without undue toxicity, incompatibility, instability, irritation,allergic response, and the like. The therapeutic and/or cosmeticcomposition is preferably transparent for transmission of the lightgenerated by the light source of the device.

The therapeutic and/or cosmetic composition may be contained in a padsuch as a gel pad or hydrogel pad. The composition may be applied priorto treatment with the device, or after treatment with the device.Preferably, the composition is present on the skin while the lightand/or ultrasound generated by the device is being applied to the skin.As used herein, the term “cosmetic composition” is intended to describecompositions for topical application to human skin, including leave-onand wash-off products. The composition may be applied, for example, bypouring, dropping, or spraying, if a liquid; rubbing on, if an ointment,lotion, cream, gel, or the like; dusting, if a powder; spraying, if aliquid or aerosol composition; or by any other appropriate means. Theterm “skin” as used herein embraces the skin of the face, eyelids,eyebrows, forehead, lips, mouth, nose, ears, neck as well as the chest,arms, legs, hands, fingers, feet, toes, back, stomach, scalp, and thelike.

The conditions that can be treated or otherwise addressed with thedevice of the present invention include various skin or cosmeticconditions including skin-aging, cellulite, enlarged pores, oily skin,folliculitis, precancerous solar keratosis, skin lesion, aging, wrinkledand sun-damaged skin, crow's feet, skin ulcers (diabetic, pressure,venous stasis), acne rosacea lesions, cellulite; photomodulation ofsebaceous oil glands and the surrounding tissues; reducing wrinkles,acne scars and reducing acne bacteria, inflammation, pain, wounds,edema, Pagets disease, primary and metastatic tumors, connective tissuedisease, manipulation of collagen, fibroblast, and fibroblast derivedcell levels in mammalian tissue, illuminating retina, neoplastic,neovascular and hypertrophic diseases, inflammation and allergicreactions, perspiration, sweating and hyper-hydrosis from eccrine(sweat) or apocrine glands, jaundice, vitiligo, ocular neovasculardiseases, bulimia nervosa, herpes, seasonal affective disorders, mood,sleep disorders, skin cancer, crigler naijar, atopic dermatitis,diabetic skin ulcers, pressure ulcers, relief of muscular pains, pain,stiffness of joints, reduction of bacteria, gingivitis, whitening teeth,treatment of teeth and tissue in mouth, wound healing. As used herein,the term “treating” or “treatment” means the treatment (e.g., whole orpartial alleviation or elimination of symptoms and/or cure) and/orprevention or inhibition of the condition.

In one aspect, the cosmetic conditions that can be addressed with thedevice of the present invention are selected from acne, skinrejuvenation and skin wrinkles, cellulite, melisma (skin brown spots ordiscoloration), and vitiligo. Many therapeutic treatments also have acosmetic component. Psoriasis, e.g., can be mild, mild-to-moderate,moderate, moderate-to-severe and severe. Any of these categories has acosmetic component, which may be responsible for severe psychologicalproblems of affected patients.

Examples of therapeutic and/or cosmetic agents that may be contained inthe therapeutic and/or cosmetic composition of the present invention aredescribed in Luebecke, U.S. Published Patent Application No.2008/0051680 and Castel, U.S. Published Patent Application No.2011/0040235, which are both incorporated herein by reference.

In another aspect, the therapeutic and/or cosmetic composition comprisesan anti-glycation agent. Examples of anti-glycation agents include oneor more of alanyl-L-histidine (L-carnosine), N-acetylcysteine,aminoguanidine, D-penicillamine, acetylsalicyclic acid (aspirin),paracetamol, indomethacin and ibuprofen and/or a functional derivativeor prodrug thereof. Other examples include beta-alanylhistamine(carcinine), N-acetyl-beta-alanylhistamine (N-acetylcarcinine), L-prolylhistamine, N-acetyl-L-carnosine, and combinations thereof.

In one aspect, the cosmetic conditions that can be addressed with thedevice of the present invention include the treatment of acneiformeruptions. The term acneiform eruption refers to a group of dermatosesincluding acne vulgaris, rosacea, folliculitis, and perioral dermatitis.Acneiform eruptions are, generally spoken, caused by changes in thepilosebaceous unit and are selected from acne aestivalis (Mallorcaacne), acne conglobata, acne cosmetics, acne fulminans (acute febrileulcerative acne), acne keloidalis (acne keloidalis nuchae, dermatitispapillaris capillitii, folliculitis keloidalis, folliculitis keloidisnuchae, nuchal keloid acne), acne mecanica, acne medicamentosa, acnemiliaris necrotica (acne varioliformis), acne vulgaris, acne with facialedema (solid facial edema), acneiform eruptions, blepharophyma,erythrotelangiectatic rosacea (erthemaotelangiectatic rosacea),excoriated acne (acne excoriée des jeunes filles, Picker's acne),glandular rosacea, gnathophyma, gram-negative rosacea, granulomatousfacial dermatitis, granulomatous perioral dermatitis, halogen acne,hidradenitis suppurativa (acne inversa, Verneuil's disease), idiopathicfacial aseptic granuloma, infantile acne, lupoid rosacea (granulomatousrosacea, micropapular tuberculid, rosacea-like tuberculid ofLewandowsky), lupus miliaris disseminatus faciei, metophyma, neonatalacne (acne infantum, acne neonatorum), occupational acne, ophthalmicrosacea (ocular rosacea, ophthalmorosacea), otophyma, persistent edemaof rosacea (chronic upper facial erythematous edema, Morbihan's disease,Rosaceous lymphedema), pomade acne, papulopustular rosacea,perifolliculitis capitis abscedens et suffodiens (dissecting cellulitisof the scalp, dissecting folliculitis, perifolliculitis capitisabscedens et suffodiens of Hoffman), perioral dermatitis, periorbitaldermatitis (periocular dermatitis), pyoderma faciale (rosaceafulminans), rhinophyma, rosacea (acne rosacea), rosacea conglobata,rosacea fulminans, SAPHO syndrome, steroid rosacea, tropical acne.

In one embodiment, the therapeutic and/or cosmetic composition comprisesan anti-acne and/or anti-rosacea agent. Examples of anti-acne andanti-rosacea agents include, but are not limited to: retinoids such astretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaicacid, and retinol; triclosan; chlorhexidine gluconate; salicylic acid;benzoyl peroxide; resorcinol; sulfur; sulfacetamide; urea; antibioticssuch as tetracycline, clindamycin, metronidazole, erythromycin;anti-inflammatory agents such as corticosteroids (e.g., hydrocortisone),ibuprofen, naproxen, and hetprofen; imidazoles such as ketoconazole andelubiol; and salts and prodrugs thereof. Other examples of anti-acneactive agents include: all forms of vitamin C (D-ascorbic acid,L-ascorbic acid or derivatives of ascorbic acid), all forms oftocopherol (vitamin E) or its derivatives, essential oils,alpha-bisabolol, dipotassium glycyrrhizinate, camphor, beta-glucan,allantoin, feverfew, flavonoids such as soy isoflavones, saw palmetto,chelating agents such as EDTA, lipase inhibitors such as silver andcopper ions, hydrolyzed vegetable proteins, inorganic ions of chloride,iodide, fluoride, and their nonionic derivatives chlorine, iodine,fluorine, and other valences, synthetic phospholipids and naturalphospholipids such as Arlasilk™ phospholipids CDM, SV, EFA, PLN, and GLA(Uniqema, ICI Group of Companies, Wilton, UK). Combinations of theforegoing are also within the scope of the present invention.

In another aspect, the therapeutic and/or cosmetic composition comprisesan antioxidant. In general, antioxidants are substances which inhibitoxidation or suppress reactions promoted by oxygen or peroxides.Antioxidants, especially lipid-soluble antioxidants, can be absorbedinto the cellular membrane to neutralize oxygen radicals and therebyprotect the membrane. In one aspect, the anti-oxidant is selected fromthe group consisting of one or more of arginine, ascorbic acid, aprodrug or derivative of ascorbic acid, ascorbyl palmitate, magnesiumascorbyl phosphate, trisodium ascorbyl phosphate, anserine, carnosine,opidine, homocarnosine and/or acetylanserine. The antioxidants useful inthe present invention are preferably selected from the group consistingof: all forms of tea or its extracts including, black, red, and greentea, all forms of vitamin A (retinol, palmitate), all forms of vitaminA₂ (3,4-didehydroretinol), all forms of carotene such as alpha-carotene,beta-carotene, gamma-carotene, delta-carotene, all forms of vitamin C(D-ascorbic acid, L-ascorbic acid, or derivatives of ascorbic acid), allforms of tocopherol such as vitamin E or its derivatives(alpha-tocopherol,3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltri-decyl)-2H-1-benzopyran-6-ol),beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocoquinone,tocotrienol. In a preferred aspect, the therapeutic and/or cosmeticcomposition includes one or more of ascorbic acid (vitamin C) oralpha-tocopherol (vitamin E) or their pharmaceutically acceptable saltsand esters.

In still another aspect, the therapeutic and/or cosmetic compositioncomprises hyaluronic acid (HA) or salt or derivative thereof. Thecomposition may comprise high molecular weight HA (greater than 1×10⁶Da), low molecular weight HA (less than about 1×10⁶ Da), or somecombination thereof. The HA may have a molecular weight ranging betweenabout 50 Da about to 2×10⁷ Da (e.g., about 50, 100, 500, 1000, 5000,10,000, 50,000, 1×10⁵, 2×10⁵, 3×10⁵, 4×10⁵, 5×10⁵, 6×10⁵, 7×10⁵, 8×10⁵,9×10⁵, 1×10⁶ Da, 5×10⁶ Da, 1×10⁷ Da, 1.5×10⁷ Da, 2×10⁷ or some rangetherebetween). The therapeutic and/or cosmetic composition may comprisea low molecular weight HA (e.g., about 10, 50, 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 10,000, 20,000, 30,000, 40,000, 50,000,60,000, 70,000, 80,000, 90,000, 1×10⁵, 2×10⁵, 3×10⁵, 4×10⁵, 5×10⁵,6×10⁵, 7×10⁵ 8×10⁵, 9×10⁵, 1×10⁶ Da or some range therebetween) incombination with a high molecular weight HA (e.g., about 1×10⁶ Da, 5×10⁶Da, 1×10⁷ Da, 1.5×10⁷ Da, 2×10⁷ Da or some range therebetween).

In one aspect, the device may be used in conjunction with a therapeuticand/or cosmetic composition comprising a hormone. Suitable hormones are,e.g., selected from estrogen, progestogen, a combination of estrogen andprogestogen, cyproterone, oestrogen, a combination of cyproterone andestrogen, drospirenone, spironolactone, and cortisone. In anotheraspect, the therapeutic and/or cosmetic composition includes a retinoid,such as vitamin A derivatives such as isotretinoin, tretinoin,adapalene, tazarotene, isotretinoin, and retinol.

In one aspect, the device may be used in conjunction with a therapeuticand/or cosmetic composition comprising an anti-aging agent. Examples ofsuitable anti-aging agents include, but are not limited to: inorganicsunscreens such as titanium dioxide and zinc oxide; organic sunscreenssuch as octyl-methoxy cinnamates; retinoids; dimethylaminoathanol(DMAE), copper containing peptides, vitamins such as vitamin E, vitaminA, vitamin C, and vitamin B and vitamin salts or their derivatives suchas ascorbic acid di-glucoside and vitamin E acetate or palmitate; alphahydroxy acids and their precursors such as glycolic acid, citric acid,lactic acid, malic acid, mandelic acid, ascorbic acid,alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid,alpha-hydroxyisocaproic acid, atrrolactic acid, alpha-hydroxyisovalericacid, ethyl pyruvate, galacturonic acid, glucoheptonic acid,glucoheptono 1,4-lactone, gluconic acid, gluconolactone, glucuronicacid, glucuronolactone, isopropyl pyruvate, methylpyruvate, mucic acid,pyruvic acid, saccharic acid, saccaric acid 1,4-lactone, tartaric acid,and tartronic acid; beta hydroxy acids such as beta-hydroxybutyric acid,beta-phenyl-lactic acid, and beta-phenylpyruvic acid; zinc and zinccontaining compounds such as zinc oxides; and botanical extracts such asgreen tea, soy, milk thistle, algae, aloe, angelica, bitter orange,coffee, goldthread, grapefruit, hoellen, honeysuckle, Job's tears,lithospermum, mulberry, peony, puerarua, nice, and safflower; and saltsand prodrugs thereof.

In one aspect, the device may be used in conjunction with a therapeuticand/or cosmetic composition comprising a depigmentation agent. Examplesof suitable depigmentation agents include, but are not limited to: soyextract; soy isoflavones; retinoids such as retinol; kojic acid; kojicdipalmitate; hydroquinone; arbutin; transexamic acid; vitamins such asniacin and vitamin C or their derivatives; azelaic acid; linolenic acidand linoleic acid; placertia; licorice; and extracts such as chamomileand green tea; and salts and prodrugs thereof.

In one aspect, the device may be used in conjunction with a therapeuticand/or cosmetic composition comprising a plant extract. Examples ofplant extracts include, but are not limited to: feverfew, soy, glycinesoja, oatmeal, what, aloe vera, cranberry, hazel witch, alnus, arnica,artemisia capillaris, asiasarum root, birch, calendula, chamomile,cnidium, comfrey, fennel, galla rhois, hawthorn, houttuynia, hypericum,jujube, kiwi, licorice, magnolia, olive, peppermint, philodendron,salvia, sasa albo-marginata, natural isoflavonoids, soy isoflavones, andnatural essential oils.

In one aspect, the device may be used in conjunction with a therapeuticand/or cosmetic composition comprising other active agents includingthose commonly used for topical treatment and in cosmetic treatment ofskin tissues, such as topical antibiotics for wounds, topical antifungaldrugs to treat fungal infections of the skin and nails, andantipsoriatic drugs to treat psoriatic lesions of the skin and psoriaticnails.

Examples of antifungal drugs include, but are not limited to:miconazole, econazole, ketoconazole, sertaconazole, itraconazole,fluconazole, voriconazole, clioquinol, bifoconazole, terconazole,butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole,clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate,nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine,elubiol, griseofulvin, and their pharmaceutically acceptable salts andprodrugs.

Examples of antibiotics (or antiseptics) include, but are not limitedto: mupirocin, neomycin sulfate bacitracin, polymyxin B, 1-ofloxacin,tetracyclines (chlortetracycline hydrochloride, oxytetracycline-10hydrochloride and tetrachcycline hydrochoride), clindamycin phosphate,gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzethoniumchloride, phenol, quaternary ammonium compounds, tea tree oil, and theirpharmaceutically acceptable salts and prodrugs.

Examples of antimicrobials include, but are not limited to: salts ofchlorhexidine, such as lodopropynyl butylcarbamate, diazolidinyl urea,chlorhexidine digluconate, chlorhexidine acetate, chlorhexidineisethionate, and chlorhexidine hydrochloride. Other cationicantimicrobials may also be used, such as benzalkonium chloride,benzethonium chloride, triclocarban, polyhexamethylene biguanide,cetylpyridium chloride, methyl and benzethonium chloride. Otherantimicrobials include, but are not limited to: halogenated phenoliccompounds, such as 2,4,4′-trichloro-2-hydroxy diphenyl ether(Triclosan); parachlorometa xylenol (PCMX); and short chain alcohols,such as ethanol, propanol, and the like.

Examples of antipsoriatic drugs or drugs for seborrheic dermatitistreatment include, but are not limited to: corticosteroids (e.g.,betamethasone dipropionate, betamethasone valerate, clobetasolpropionate, diflorasone diacetate, halobetasol propionate,triamcinonide, dexamethasone, fluocinonide, fluocinolone acetonide,halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisonevalerate, hydrocortisone butyrate, alclometasone dipropionate,flurandrenolide, mometasone furoate, methylprednisolone acetate),methotrexate, cyclosporine, calcipotriene, anthraline, shale oil andderivatives thereof, elubiol, ketoconazole, coal tar, salicylic acid,zinc pyrithione, selenium sulfide, hydrocortisone, sulfur, menthol, andpramoxine hydrochloride, and salts and prodrugs thereof.

Examples of anti-inflammatory agents include, but are not limited to:suitable steroidal anti-inflammatory agents such as corticosteroids suchas hydrocortisone, hydroxyltriamcinolone alphamethyl dexamethasone,dexamethasone-phosphate, beclomethasone dipropionate, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclarolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene)acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenalone acetonide, medrysone, amciafel, amcinafide,betamethasone, chlorprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylproprionate, hydrocortamate, meprednisone,paramethasone, prednisolone, prednisone, beclomethasone dipropionate,betamethasone dipropionate, triamcinolone, and salts are prodrugsthereof. The preferred steroidal anti-inflammatory for use in thepresent invention is hydrocortisone. A second class of anti-inflammatoryagents which is useful in the compositions of the present inventionincludes the nonsteroidal anti-inflammatory agents.

Other active agents include, but are not limited to: wound healingenhancing agents, such as recombinant human platelet-derived growthfactor (PDGF) and other growth factors, ketanserin, iloprost,prostaglandin E₁ and hyaluronic acid, scar reducing agents such asmannose-6-phosphate, analgesic agents, anesthetics, hair growthenhancing agents such as minoxidil, hair growth retarding agents such aseflornithine hydrochloride, antihypertensives, drugs to treat coronaryartery diseases, anticancer agents, endocrine and metabolic medication,neurologic medications, medication for cessation of chemical additions,motion sickness, protein and peptide drugs.

The amount of the active agent in the therapeutic and/or cosmeticcomposition will depend on the active agent and/or the intended use ofthe device. In one embodiment, the carrier contains a safe and effectiveamount of the active agent, for example, from about 0.001 percent toabout 20 percent, by weight, such as from about 0.01 percent to about 5percent, by weight, of the carrier. As used herein, “safe and effectiveamount” means an amount of the ingredient or of the compositionsufficient to provide the desired benefit at a desired level, but lowenough to avoid serious side effects. The safe and effective amount ofthe ingredient or composition will vary with the area being treated, theage and skin type of the end user, the duration and nature of thetreatment, the specific ingredient or composition employed, theparticular pharmaceutically-acceptable carrier utilized, and likefactors.

In one aspect, for the treatment of acne, the device of the presentinvention preferably emits light in the range between about 350 and 900nm, preferably between about 380 and 850 nm, more preferably betweenabout 400 and 850 nm, and even more preferably between about 400 and 830nm. Further, the preferred light for the treatment of acne is purplelight. The preferred purple light has emission wavelengths for thetreatment of acne of about 390, 391, 392, 393, 394, 395, 396, 397, 398,399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412,413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426,427, 428, 429 and 430 nm. For example, 414 and 415 nm are particularlysuitable in order to kill P. acnes bacteria and to help cure existingblemishes and to prevent further outbreaks. Studies on the applicationof phototherapy to treat acne have revealed that a combination ofdifferent wavelengths or ranges of wavelengths are particularly suitableto treat acne efficiently. For example, a combination of red light andpurple light is may be used to treat acne. The red light is preferablyselected from the range between about 590 to 750 nm, more preferablybetween about 600 and 720 nm, and even more preferably between 620 and700 nm. Two further preferred wavelengths for the treatment of acne are633 and 660 nm. The light at about 633 to 660 nm increases cellularmetabolism, triggers collagen synthesis for scar repair and remodelingand increases Superoxide dismutase which acts as an oxygen radicalscavenger, which decreases inflammation. A further effect is theincrease of nitric oxide (NO) synthesis which increases microvascularperfusion further impacting the cleansing and washout of tissues whereinflammatory substances have aggregated. The purple light can beselected from the wavelengths as described above.

The ultrasonic energy should be applied over the treatment site (such asan acne-infected skin) preferably in the range of about 2 kHz to 200 kHzand more preferably in the 45 to 90 kHz range. These frequencies providethe breakup of bacterial plaque to further cleanse the tissue, whileopening channels through the stratum corneum allowing the passage oftherapeutic active agents. Thus, the effects of the light, ultrasoundand active therapeutic/cosmetic agent act in a synergistic fashion andare complimentary. Additionally, heat may be provided using a heaterlayer in contact with the skin to treat acne eruptions in an effectivemanner. Electrical current may also be applied to add an iontophoreticcomponent to assist the drive of the therapeutic active agents assumingthey are ionic.

For the treatment of whiteheads, the device preferably emits light ofabout 500 nm or light in the range between 500 and 700 nm. A whitehead,which is also called closed comedone, is a follicle that is filled withthe same material, sebum, but has a microscopic opening to the skinsurface. Since the air cannot reach the follicle, the material is notoxidized, and remains white. This is an application where the heatingelement of the present invention is particularly effective.

In another aspect, for the treatment or prevention of cellulite, thedevice preferably emits light in the range between 400 and 1000 nm,preferably in the range between 400 and 900 nm, more preferably in therange between 450 and 900 nm, and even more preferably in the rangebetween 500 and 850 nm. For the treatment or prevention of cellulite,the device preferably applies ultrasound at a frequency of between about25 kHz and 80 kHz to cause a breakup of the cellulite matrix. Cellulitedescribes a condition that is claimed to occur in most women, where theskin of the lower limbs, abdomen, and pelvic region becomes dimpled. Theuse of high frequency ultrasound at about 1 to 5 MHz is also effectivein heating the areas of cellulite to liquefy the structure which canthen through retrograde massage be reabsorbed in the lymphatic channels.The low frequency ultrasound opens channels through the stratum corneumallowing the passage of therapeutic active agents that assist in thebreakup and reabsorption of the cellulite matrix. Thus, the effects ofthe light, ultrasound and active therapeutic and/or cosmetic agent actin a synergistic fashion and are complimentary. Additionally, heat maybe provided using a heater layer in contact with the skin which assistsin the liquefaction of the cellulite matrix.

For the treatment or prevention of skin aging and fine lines andwrinkles, the device preferably emits light in the range between 400 and950 nm. Preferably, the wavelength is in the range between 550 and 900nm, such as between 600, 630, 660 or some range therebetween. In anotheraspect, for the treatment and/or prevention of skin aging, the deviceemits infrared light in the range between 780 and 1060 nm. The light atabout 633 to 660 nm increases cellular metabolism, triggers collagensynthesis for scar repair and remodeling and increases Superoxidedismutase which acts as an oxygen radical scavenger, which decreasesinflammation. A further effect is the increase of NO synthesis whichincreases microvascular perfusion further impacting the cleansing andwashout of tissues where inflammatory substances have aggregated whileimproving tissue nutrition. The use of pulsed subthermal high frequencyultrasound at about 1 to 5 MHz at 20% duty factors in the range of 0.5w/cm² is also effective in stimulating tissue regeneration and is oftenused in this application. The low frequency ultrasound opens channelsthrough the stratum corneum allowing the passage of therapeutic activeagents such as vitamin C, hyaluronic acid large, and other activesagents that assist in the rebuilding of the collagen and elastin matrix.Thus, the effects of the light, ultrasound and active therapeutic and/orcosmetic agent act in a synergistic fashion and are complimentary.Additionally, heat may be provided using a heater layer in contact withthe skin which assists further in the treatment of wrinkles through aheat and stretch mechanism. That is, once the tissue reaches theviscoelastic temperature of about 40-41° C., manual stretching of thewrinkle tends to iron it out. If the stress is maintained during cooldown, the wrinkle will flatten and maintain the new elongation of thecollagen. In another aspect, electrical current can be applied toprovide additional iontophoretic drive in combination with the lowfrequency ultrasound to further penetrate the active agents. If thecurrent is an AC or pulsed current, it may be used to decrease muscledisuse atrophy or muscle hypertonicity to remodel the underlying musclestructure and thereby decrease wrinkles in a similar manner (withrespect to the aesthetic result) that Botox or muscle exercise wouldaffect the tissue structure.

In one aspect, the composition includes a photosensitizing medicine foruse in phototherapy treatments. In this case, the device activates thephotosensitizing medication. The photosensitizing medicine can be aliquid, cream or intravenous drug. For pre-cancer or cancer treatment,for example, the photosensitizing medicine is preferably absorbed byatypical or cancerous cells. When the photosensitizing medicine isirradiated with light, activated oxygen molecules are produced which candestroy nearby cells. The ultrasonic field provides transport of thetherapeutic medication through the stratum corneum to increase itsefficacy as opposed to topical application.

In another aspect, the composition is a polymerizable composition thatis polymerized under the action of the light generated from the lightsource, such as in Samain, European Patent No. 2252256. Thus, in anexemplary embodiment, the invention is directed to a cosmetic treatmentmethod comprising: (a) depositing a composition on the skin, saidcomposition being polymerizable under the action of a light stimulus;(b) placing the device of the present invention (such as in the form ofa patch, bandage, and the like) over the composition; and (c) directinga light from the device to cause polymerization of the composition.

Modulation of Frequencies for Transdermal Transport

As discussed above, the low frequency ultrasound provided by the deviceprovides cavitational effects in the skin, which improves drug deliveryinto and through the skin. It will be appreciated that the ultrasoundsource comprises an ultrasonic transducer that may be operated atdifferent frequencies in order to maximize or otherwise improvetransport of various therapeutic and/or cosmetic agents in acomposition. For example, it will be appreciated that therapeutic and/orcosmetic agent “A” may be optimally transported at ultrasound frequencyf_(A) with an optional ultrasound modulation frequency f_(MA) whiletherapeutic and/or cosmetic agent “B” may be optimally transported atultrasound frequency f_(B) with an optional ultrasound modulationfrequency f_(MB). The different ultrasound frequencies (and optionalultrasound modulation frequencies) result in different cavitationeffects and create different sizes of distortions in the stratumcorneum, allowing different sizes of molecules and compounds to passthrough the skin. Thus, the present invention contemplates that theultrasound frequencies and/or the modulation frequencies can be variedcontinuously or in stages during operation. That is, the presentinvention contemplates that the transducer can operate at multiplefrequencies (e.g., continuously over a selected range of frequencies orat one or more pre-determined frequencies).

Further, the device may be programmed using an electronic control moduleto operate in cycles of different frequencies that correspond to thoseassociated with the various therapeutic and/or cosmetic agents. Forexample, the device may be programmed to operate at an ultrasoundfrequency f_(A) for a first period of time (in order to maximizetransport of therapeutic and/or cosmetic agent A) and then operate at anultrasound frequency f_(B) for a second period of time (in order tomaximize transport of therapeutic and/or cosmetic agent B). As anotherexample, the device may be programmed to operate at an ultrasoundfrequency f_(A) with an ultrasound modulation frequency of f_(MA) for afirst period of time (in order to maximize transport of therapeuticand/or cosmetic agent A) and then operate at an ultrasound frequencyf_(B-US) with an ultrasound modulation frequency f_(MB) for a secondperiod of time (in order to maximize transport of therapeutic and/orcosmetic agent B). As yet another example, the device may be operated atan ultrasound frequency f_(A) with an ultrasound modulation frequency off_(MA) for a first period of time followed by a change in the ultrasoundmodulation frequency only to f_(MB) for a second period of time. Thecycling and patterns of the frequency provides significant benefits intransporting compositions containing multiple therapeutic and/orcosmetic agents through the skin surface. The amount of time at eachfrequency may also be programmed into the electronic control modulebased on the percentage composition of the therapeutic and/or cosmeticagent and the diffusion rate through the skin for the therapeutic and/orcosmetic agent. It will be appreciated that multiple therapeutic and/orcosmetic agents may be delivered using similar techniques to optimizeeach therapeutic and/or cosmetic agent.

In another aspect, the light source may be pulsed at variousfrequencies, including the modulation or fundamental frequency of theultrasonic transducer. The pulsation is preferably synchronized tomaximize cavitation effects on the cellular membranes and the stratumcorneum. The wavelength of the light is selected to optimize the healingand biostimulative effects in the tissue and the light modulationfrequencies are synchronized with the frequencies of the ultrasonicmodulation or the fundamental frequency of the ultrasonic transducer.This synergistic effect enhances the shear waves and cavitation effectsin the tissue when the light source is pulsed synchronously with theultrasonic wave modulation.

Thus, it will be appreciated that the light source of the device may beoperated at different wavelengths modulated at different frequencies inorder to maximize transport of various therapeutic and/or cosmeticagents in a composition. For example, it will be appreciated thattherapeutic and/or cosmetic agent “A” may be optimally transported atlight wavelength λ_(A) and pulsed with an optional light modulationfrequency f_(MA) while therapeutic and/or cosmetic agent “B” may beoptimally transported at wavelength 4 with an optional light modulationfrequency f_(MB). The different light wavelengths (and optional lightmodulation frequencies) result in different cavitation effects andcreate different sizes of distortions in the stratum corneum, allowingdifferent sizes of molecules and compounds to pass through the skin.Thus, the present invention contemplates light having variouswavelengths and the modulation frequencies can be varied continuously orin stages during operation. That is, the present invention contemplatesthat the light source can operate at multiple wavelengths (e.g., over aselected range of wavelengths or at one or more pre-determinedwavelengths). Further, the device may be programmed using the electroniccontrol module to operate in cycles of different wavelengths thatcorrespond to those associated with the various therapeutic and/orcosmetic agents. For example, the device may be programmed to operate ata light wavelength λ_(A) for a first period of time (in order tomaximize transport of therapeutic and/or cosmetic agent A) and thenoperate at a light wavelength λ_(B) for a second period of time (inorder to maximize transport of therapeutic and/or cosmetic agent B). Asanother example, the device may be programmed to operate at a lightwavelength λ_(A) with a light modulation frequency of f_(MA) for a firstperiod of time (in order to maximize transport of therapeutic and/orcosmetic agent A) and then operate at a light wavelength λ_(B) with alight modulation frequency f_(MB) for a second period of time (in orderto maximize transport of therapeutic and/or cosmetic agent B). As yetanother example, the device may be operated at a light wavelength λ_(A)with a light modulation frequency of f_(MA) for a first period of timefollowed by a change in the light modulation frequency only to f_(MB)for a second period of time. This may be repeated for third, fourth,fifth times, etc. for other active agents. The cycling and patterns ofthe light energy wavelengths and modulation frequencies providesignificant benefits in transporting compositions containing multipletherapeutic and/or cosmetic agents through the skin surface. The amountof time at each wavelength and/or modulation frequency may also beprogrammed into the electronic control module based on the percentagecomposition of the therapeutic and/or cosmetic agent and the diffusionrate through the skin for the therapeutic and/or cosmetic agent.

To ascertain the appropriate modulation of the ultrasound for a giventherapeutic and/or cosmetic agent, microdialysis can be used. Likewise,the effects of pulsing the light at various modulation frequencies mayalso be determined using this method. In general, a compositioncontaining the therapeutic and/or cosmetic agent is placed on the skinor tissue surface in a conductive ultrasound gel. The ultrasonictransducer is placed over the composition and the skin or tissue, andthe transducer is activated at the appropriate dose and test frequency.Sterile water is pumped through a microdialysis probe implantedapproximately 2 mm under the skin under the transducer. See, e.g.,Klimowicz, Evaluation of Skin Penetration of Topically Applied Drugs inHumans by Cutaneous Microdialysis, J Clin Pharm Ther. April; 32(2):143-8 (2007); and Ault et al., Microdalysis Sampling for theInvestigation of Dermal Drug Transport, Pharm Res. October 9(10):1256-61 (1992).

The ultrasound frequencies, ultrasound modulation frequencies, lightwavelengths, and light modulation frequencies that have been optimizedfor the transdermal delivery for each therapeutic and/or cosmetic agentof interest are programmed into the electronic control module. Thus, itis contemplated that the device can apply a frequency (ultrasound andlight) for each therapeutic and/or cosmetic agent. That is, assumingthat the transdermal delivery of therapeutic and/or cosmetic agent A isoptimal at a first ultrasonic frequency f_(A) (with an optionalultrasonic modulation frequency f_(MA)) and a first light wavelengthλ_(A) (with pulsing at an optional light modulation frequency of f_(MA))and the transdermal delivery of therapeutic and/or cosmetic agent B isoptimal at a second ultrasonic frequency f_(B) (with an optionalultrasonic modulation frequency f_(MB)) and a second light wavelengthλ_(B) (with pulsing at an optional light modulation frequency off_(MB)), then the device is programmed to operate in at least bothmodalities. In one aspect, the ultrasound and light are modulated at thesame frequency.

Phototherapy

The device of the present invention can be used to provide phototherapyto a patient. As a result of the wavelength of the light, and thefrequency of pulsation, and the energy delivery from the light source,there results in the body a large number of physiological responses.These physiological responses include, for example, acceleration of theproduction of procollagen resulting in enhanced collagen synthesisthrough selective action on collagen gene expression at thetranscriptional level. This is a likely sequel to elevations ofprocollagen mRNA levels resulting in alterations in the chromatinstructure. There is also theorized to be increased cross-linking ofexisting collagen molecules and improved organization of functionalcollagen fibers. Also, it is theorized that the device stimulatesmacrophages (a type of white blood cell) to release factors thatstimulate fibroblast replication and proliferation (e.g., monokines).Cellular effects which occur include mitochondrial hyperplasia, theappearance of cytoplasmic microfilament bundles, and the deposition ofan abundant fibrillar matrix in pericellular regions. A cellularphenotype of the fibroblast, the myofibroblast, is generated. This cellis found in granulation tissue, and its primary role occurs in theremodeling phase of wound healing, including contractile activity inaddition to the synthesis of collagen. The photothermal treatment devicethereby accelerates the formation of a functional scar. See generally,Shapiro, U.S. Pat. No. 6,187,029. Pulsed light or ultrasonic stimulationalso has the ability to stimulate underlying neural tissue, includingsympathetic, parasympathetic and sensory nerves. Depending on the pulseparameters selected, nerves may be selectively stimulated to increase ordecrease circulation and blood flow to assist in the treatment of tissuerepair or modulation of inflammatory response or blocking orreabsorprion of edema. The device of the present invention may beprogrammed with a variety of wavelengths, ultrasound frequencies, dutyfactors, pulse rates and amplitudes to achieve the desired physiologicaleffects described herein.

In another aspect, the device is well adapted to provide light energy,ultrasound, and heating of about 1 to 4° C. (e.g., via light energy fromthe light source, ultrasound from the high frequency ultrasonictransducer, and heat from the flexible transparent heater layer, orcombinations thereof). It is known that high frequency ultrasound causesthermal effects in the skin and superficial tissue. This heat applied tothe tissue triggers HSPs which act to reduce cellular death due toultraviolet light exposure. Among other things, light energy in the nearinfrared and red visible regions provides a photoprotective effect onthe subsequent lethal effects of exposure to UV light. The combinationis highly synergistic to reducing UV photoaging and repairing itseffects. If the device is also used with low frequency ultrasound,phonophoresis of Vitamin C and other substances can be effected tofurther accelerate the repair and photoprotective process.

Power Supply, Drive Circuit and Control Module

Each device of the present invention is driven and controlled by anelectronic circuit that includes a power supply, drive circuit andcontrol module. The electronic circuit may be provided in a separatehousing electrically connected to the device or may be built into theflexible material that mounts the device or an array of the devices.

The power supply may be any power supply capable of supplying sufficientpower to activate the light source, the ultrasonic transducer(s), theheater layer and/or the electrical stimulation layer of each device. Thepower supply may comprise a disposable or rechargeable battery, solarcell, fuel cell, an adapter, or may be powered by the power grid. Thelight source is preferably driven by DC or pulsed DC; however, the lightsource may alternatively be driven by AC. The ultrasonic transducer(s)are preferably driven by AC to deliver the low and/or high frequencyultrasound, although pulsed DC may be used to deliver low frequencyultrasound. The heater layer may be driven by AC, DC or pulsed DC tocause resistive heating across the device. The electrical stimulationlayer is preferably driven by DC or pulsed DC to provide iontophoresis,or may be driven by pulsed AC or pulsed DC to provide relaxation ortoning of the muscles. It should be understood that the electricalstimulation layer typically functions as a conductive electrode and isused in combination with a conductive return electrode to provide thedesired electrical stimulation, as discussed above. One skilled in theart will understand that the output voltages and current levels of theDC, AC, pulsed DC and pulsed AC referenced above control the peak outputof each layer of the device, which in combination with the treatmenttime control the dose.

In one embodiment, the control module is incorporated into theelectronic circuit connected to the device or built into the flexiblematerial that mounts the device (referred to as an “internal controlmodule”). FIG. 12 is a block diagram of an exemplary electronic circuitfor this embodiment. As can be seen, the device includes a light source,an ultrasonic transducer (low frequency and/or high frequency), a heaterlayer, and a conductive/electrical stimulation layer. Of course, itshould be understood that the device could include only one or anycombination of these elements. In one aspect, the device includes only alight source. In another aspect, the device includes only a lowfrequency ultrasonic transducer. In another aspect, the device includesonly a high frequency ultrasonic transducer. In yet another aspect, thedevice includes only a dual frequency ultrasonic transducer. Othercombinations will be apparent to one skilled in the art.

Each element of the device is independently controlled by amicrocontroller (discussed below). Some elements may be directlyconnected to the microcontroller (DC output from the microcontroller),some elements may be connected to the microcontroller through anamplifier (AC output from the microcontroller), and some elements may beconnected to the microcontroller through an oscillator that converts DCto AC in combination with an amplifier (DC output from themicrocontroller). It should be understood that a variety of othercircuit designs are possible and within the knowledge of one skilled inthe art. The microcontroller is connected to one or more I/O devices,such as an LED that provides an indication of whether the device ison/off or an audio buzzer that alerts the user upon completion of aparticular treatment. An on/off switch may also be provided to power thedevice.

Each element of the device is independently controlled by amicrocontroller in accordance with a preprogrammed treatment cycle thatprovides a sequence of light, ultrasound, heat and/or electricalstimulation at a fixed dose. For example, the microcontroller may bepreprogrammed for treatment of a specific cosmetic disorder, such asacne, psoriasis, and the like. The microcontroller may independentlycontrol the light source by adjusting the activation and deactivation ofthe light source, voltage, current, light wavelength, pulse width,modulation frequency, duty factor, and light treatment time. Likewise,the microcontroller may independently control an ultrasonic transducerby adjusting the activation and deactivation of the transducer,ultrasound treatment time, ultrasound frequency, ultrasound modulationfrequency, etc. In addition, the microcontroller may control theelectrical stimulation output for iontophoresis, as well as thetemperature of the heater layer by adjusting the drive current to thegraphene embedded in the layer. One skilled in the art will appreciatethat other operating parameters may also be controlled by themicrocontroller in accordance with the present invention.

In another embodiment, all or a portion of the control functionality isprovided by an external control device (referred to as an “externalcontrol module”) that enables manual adjustment of the operatingparameters of the device based on user input. FIG. 13 is a block diagramof an exemplary electronic circuit for this embodiment. As can be seen,the electronic circuit is similar to that shown and described inconnection with FIG. 12, with the exception that the controlfunctionality is not preprogrammed into the microcontroller. Instead,the microcontroller is connected to a communication module that enableswired or wireless communication with an external control device. Theexternal control device may comprise a mobile communication device(e.g., a smart phone), a tablet computer, a laptop computer or any otherdevice capable of executing a suitable control application. The externalcontrol device may in turn communicate over a communication network(e.g., the Internet cloud) in order to access applications or datahosted on a remote server. The communication module may communicate withthe external control device over any suitable communication system,including network, USB and serial port communications, custom connectorsand protocols such the iPhone or iPad connectors, Radio FrequencyIdentification (RFID), TransferJet, Dedicated Short Range Communications(DSRC), EnOcean, Near Field Communication (NFC), wireless sensornetworks, ZigBee, EnOcean, Personal Area Networks (PAN), WirelessPersonal Area Networks (WPAN) such as IrDA, Wireless USB, Bluetooth,Z-Wave, ZigBee, or Body Area Network, Wireless Sensor Networks (WSN),Ultra-Wideband (UWB) (such as UWB from WiMedia Alliance), Wireless LocalArea Networks (WLAN) such as Wi-Fi products based on IEEE 802.11standards, High Performance Radio LAN (HiperLAN), Wireless MetropolitanArea Networks (WMAN), Local Multipoint Distribution Service (LMDS),Worldwide Interoperability for Microwave Access (WiMAX), and HighPerformance Radio Metropolitan Area Network (HiperMAN). In a preferredaspect, the communication module communicates with the external controldevice via a low energy Bluetooth connection. As can be seen, themicrocontroller is also connected to one or more I/O devices (asdescribed above), including a touchscreen display that enables directcontrol of the device or operates as a slave to the external controldevice. As such, the control module may comprise a combination of anexternal control module (via the external control device) and aninternal control module (via the touchscreen display). The externalcontrol device may also be connected to the Internet cloud where it canaccess stored data from previous use by the user or other users of thedevice, more intensive computing to evaluate treatment parameters andfor user data management. The external control device may also be usedto take photographs of the user's skin or other body parts and usesensors present in the external control device to provide further datasources for the user data which can be maintained in the device or inthe cloud.

In this embodiment, the control module is controlled via an input deviceto enable manual adjustment of the operating parameters of each of theelements of the device. The input device may be provided on the externalcontrol device (via a keyboard, keypad, mouse, touchscreen display,buttons, or other input devices) or on one of the I/O devices (e.g., thetouchscreen display) of the electronic circuit. The input device mayenable selection of the treatment to be provided, the treatment time,the intensity of the treatment, treatment dose, the spectral output ofthe device, the age of the patient and/or the cosmetic application. Theinput device may show the system diagnostics, verification of theinterface type (i.e., validation that the therapeutic and/or cosmeticcomposition, such as one present in a gel or gel pads, is matched to thedevice and authenticated as meeting the required specifications andauthenticity, and are in appropriate contact to the skin). The inputdevice may demonstrate sensor information relative to pre-therapeuticand post-therapeutic efficacy and safety information during operation.The input device may also enable entry of desired control points ormanual adjustment of the settings, such as target, maximum and/orminimum temperature, light intensity, ultrasound intensity, and time oftreatment. The system software may maintain archived patient/client dataincluding treatment records, sensor data, treatment recommendations(e.g., the patient should drink more water if the patient is dehydrated,the patient should apply a certain therapeutic and/or cosmeticcomposition to the patient's skin based on skin melanin content),photography and other user data which may be obtained from the inputdevices.

The control module also includes a screen or other type of output devicethat may be used to communicate dosing information, display informationon device performance, and set certain operating parameters of thedevice. The screen may also provide information concerning thetreatment, the temperature of one or more locations on the patient, theexposure area of patient, the length of the treatment cycle, the timeremaining in the treatment cycle, the light intensity setting of thelight source, the ultrasound intensity setting of the transducer, thecumulative time of multiple treatments by the device, and otherinformation concerning the settings and operation of the device. Thescreen may also provide information concerning preprogrammed treatmentcycles for various phototherapy treatments.

The device may be used in a number of treatment sessions that togetherresult in an overall treatment time. For such cases, the control modulemay include at least one timer configured to measure session time andoverall treatment time or both. The timer may be used simply to monitorthe session time or overall treatment time or may be used to deactivatethe device after completion of a session or overall treatment.

In another embodiment, the control module may operate based uponpreprogrammed treatment cycles or allow dynamic control of a treatmentcycle based upon user input or input from various sensors connected tothe control module. FIG. 14 is a block diagram of an exemplaryelectronic circuit for this embodiment. As can be seen, the electroniccircuit is similar to that shown and described in connection with FIG.13, with the addition of one or more sensors that operate in a closedloop to provide feedback to the microcontroller. The feedback maycomprise various types of signals, for example, electrical, chemical,mechanical, or pneumatic, that correspond to the parameter being sensed.Exemplary sensors include, but are not limited to, impedance measurementsensors, RFID sensors, digital signature sensors, temperature sensors,light emission spectrum sensors, pressure sensors, light intensitysensors, infrared temperature sensors, electrical impedance sensors,ultrasonic transmitters and receivers, skin hydration sensors, skinsebum level sensors, skin melanin content sensors, skin elasticitysensors, skin pH sensors, skin color sensors, skin glossiness sensors,skin friction sensors, and skin fluorescence sensors, as well as othersensors known in the art. Certain sensors may be built into the layersof the device, while other sensors may be applied to the tissue surfaceand protrude through the hydrogel.

The sensors may be used alone or in combination, for example, todetermine the patient's overall exposure to a treatment by sensing theintensity of the light wavelengths and ultrasound frequencies over timeand the total exposure of all light and ultrasound over time. Thesensors may be used in a positive or negative feedback loop to controldosage and monitor effectiveness of the device for a desiredapplication.

As an example, measurement of skin fluorescence would allow monitoringof the survival of the acne bacterium, whereby the dose would be variedor terminated based on the bacterial kill rate. The acne bacterium givesoff a florecense in the red spectrum of 600-700 nm (typically 630 nm)when illuminated with purple light of around 400-450 nm (typically 415nm). If a photo sensor is used to detect the red wavelength, then thefeedback can be used to control the dose, i.e., a longer dose until thedesired kill percentages occur. Detection diodes using diode printedinks could also be imbedded in the assembly for the purpose ofdetection. In this case, the system would pulse the purple lightfollowed by an immediate activation of the array in detection mode tolook at the red light. One skilled in the art will appreciate that thisconcept could also be used to detect other photonics tissueinteractions.

Infrared sensors could be used to detect the surface or depth skintemperature to maintain patient safety from skin burns by acting as adose control parameter during operation of the device. If the tissuegets too hot, the intensity of the light and/or ultrasound could bedecreased. Temperature measurement with infrared sensors could also beused to reach or maintain a target tissue temperature (e.g., 38° C. formild heat, 39° C. for moderate heat, or 41° C. for vigorous heat). Thedose of the light and/or ultrasound could be adjusted during treatmentto achieve or maintain the target tissue temperature. If it is desiredto deliver a fixed level of energy (e.g., 2 joules/cm²) to the tissue,the treatment time could be increased commensurate with the decrease inthe dose. The opposite is also true up to the temperature safety limitsor to the maximum limit tissue temperature.

Impedance measurement sensors could also be used to control dosage. Forexample, inflamed tissue is more conductive than non-inflamed tissue.This data may be used to control the dose of the light and/orultrasound. Typically, if the tissue is more inflamed, the dose of lightand/or ultrasound will be decreased. Impedance measurement sensors couldalso be used to measure skin hydration levels whereby the light and/orultrasound is actuated until a desired hydration level has beenachieved.

Impedance measurement sensors could also be used to determine if thehydrogel layers are correctly attached to the skin and/or are not driedout. Impedance measurement sensors could also be used to identify if thehydrogel used in a treatment is a particular proprietary blend. This maybe important from a safety standpoint and/or to ensure that the correcthydrogel is being used in the treatment.

Skin contact and conductive media sensors may be provided to validatethat authentic media is being applied and that it is in proper contactwith the device and the skin surface to ensure appropriate therapeuticoutcomes.

Ultrasonic transmitters and receivers can be used to measure thethickness of the dermis and epidermis, the tissue edema, and theultrasound attenuation in tissue. This information can be used for dosecontrol of the ultrasonic and light applied by the device.

In another embodiment, the control module is operable to control aplurality of the devices of the present invention arranged in an array.FIG. 15 is a block diagram of an exemplary electronic circuit for thisembodiment. As can be seen, the electronic circuit is similar to thatshown and described in connection with FIG. 13, with the addition of amain controller that controls each device in the array. Preferably, eachdevice in the array is assigned a logical address whereby the maincontroller individually controls the devices through their logicaladdresses. As such, the main controller may selectively drive eachdevice differently from other devices by, for example, selectivelyvarying a drive voltage or a drive current of the device. In addition,as discussed above, each element of each device may be independentlycontrolled by the associated microcontroller. Thus, the array can beprogrammed to deliver a desired sequence of light and/or ultrasoundfrequencies, in pulsed or continuous mode, such that the light and/orultrasound field moves across the array in a preset pattern and at apreset speed. In addition, the array can be programmed to deliver adesired sequence of heat and/or electrical stimulation in combinationwith the light and/or ultrasound field.

Various exemplary embodiments of the device of the present inventionwill now be described.

First Exemplary Embodiment

FIG. 4 illustrates a first exemplary embodiment of the device of thepresent invention. The device 110 comprises a light source formed on atransparent substrate 120 and an ultrasonic transducer formed on top ofthe light source. The light source comprises a flexible light emitter140 located between an anode 150 and a cathode 160. The ultrasonictransducer comprises a flexible ultrasound emitter 130 located betweenthe cathode 160 (common cathode with the flexible light emitter) and ananode 170. Various power sources are provided so that DC or pulsed DC isused to power the light source, while AC is used to power the ultrasonictransducer. Further, a transparent barrier layer 180 protects theflexible light emitter 140 from moisture and oxygen.

In this exemplary embodiment, the flexible light emitter 140 comprisesan OLED or printable LEDs, and the flexible ultrasound emitter 130comprises PiezoPaint™ material (Meggitt PLC). Both the substrate 120 andthe anode 150 are transparent. The substrate is comprised of atransparent silicon rubber, and also serves as a matching layer for theultrasound. The anode 150 is comprised of ITO. Light generated from theflexible light emitter 140 is emitted through the transparent anode 150and substrate 120 such that the device has a “bottom” light emittingconfiguration. Also, the common cathode 160 and the anode 170 arecomprised of a conductive metal such as silver. The barrier layer iscomprised of Flexent film (Konica Minolta). A therapeutic and/orcosmetic composition as described above may be placed between thesubstrate 120 and the patient's skin.

Second Exemplary Embodiment

FIG. 5 illustrates a second exemplary embodiment of the device of thepresent invention. The device 210 comprises a light source formed on afirst surface 222 a of a substrate 220 (i.e., the surface facing towardsthe patient's skin) and an ultrasonic transducer formed on a secondsurface 222 b of the substrate 220 (i.e., the surface facing away fromthe patient's skin). The light source comprises a flexible light emitter240 located between an anode 250 and a cathode 260 a. The ultrasonictransducer comprises a flexible ultrasound emitter 230 located between acathode 260 b and an anode 270. Various power sources are provided sothat DC or pulsed DC is used to power the light source, while AC is usedto power the ultrasonic transducer. Further, a transparent barrier layer280 protects the flexible light emitter 240 from moisture and oxygen.The barrier layer 280 is formed on the light source, but may optionallyalso cover the ultrasonic transducer as illustrated.

In this exemplary embodiment, the flexible light emitter 240 comprisesan OLED or printable LEDs, and the flexible ultrasound emitter 230comprises PiezoPaint™ material (Meggitt PLC). The substrate 220comprises a Mylar film and a silver nanolayer is coated on each side toform the cathode 260 a of the light source and the cathode 260 b of theultrasonic transducer. The silver nanolayer is highly reflective to thelight generated by the flexible light emitter 240 such that the light isdirected towards the skin of the patient. Both the barrier layer 280 andthe anode 250 are transparent. The barrier layer 280 is comprised ofWillow transparent flexible glass (Dow Corning). The anode 250 iscomprised of ITO. Light generated from the flexible light emitter 240 isemitted through the transparent anode 250 and barrier layer 280 suchthat the device has a “top” light emitting configuration. The anode 270is comprised of a conductive metal such as silver. A therapeutic and/orcosmetic composition as described above may be placed between thebarrier layer 280 and the patient's skin.

Third Exemplary Embodiment

FIG. 6 illustrates a third exemplary embodiment of the device of thepresent invention wherein, for simplicity, the various layers/componentsof the device are shown in a non-staggered stacked arrangement. Thisdevice is the same as the device shown in FIG. 5, but is furthermodified in one or more of four optional ways, as discussed below.

As with the device shown in FIG. 5, the device 310 includes a lightsource formed below a substrate 320 and an ultrasonic transducer formedabove the substrate 320. The light source comprises a flexible lightemitter 340 located between an anode 350 and a cathode 360 a. Theultrasonic transducer comprises a flexible ultrasound emitter 330located between a cathode 360 b and an anode 370. Various power sourcesare provided so that DC or pulsed DC is used to power the light source,while AC is used to power the ultrasonic transducer. For simplicity, thepower sources and wiring are not shown. Further, a transparent barrierlayer 380 protects the flexible light emitter 340 from moisture andoxygen.

In this exemplary embodiment, the device 310 is optionally modified toinclude a transparent matching layer 335 located between the ultrasonictransducer and the skin. As discussed above, it will be appreciated thatone or more matching layers may be incorporated into the device.Further, the matching layer 335 may include a graphene element (notshown) to provide for heating of the skin. As another option, in thisembodiment, an ultrasound reflective layer 375 is located above thetransducer, i.e., between the surface of the device facing away from theskin and the ultrasonic transducer. In addition, in this embodiment, thedevice optionally includes a micro-lens array or scattering layer 345for improving the output efficiency of the light source. Lastly, in thisembodiment, the device is optionally encapsulated in a flexible polymeror silicon rubber 390. A therapeutic and/or cosmetic composition asdescribed above may be placed between the matching layer 335 and thepatient's skin.

Fourth Exemplary Embodiment

FIG. 7 illustrates a fourth exemplary embodiment of the device of thepresent invention wherein, for simplicity, the various layers/componentsof the device are shown in a non-staggered stacked arrangement. Thedevice 410 comprises a light source formed above a transparent substrate420 and two ultrasonic transducers formed above the light source. Thelight source comprises a flexible light emitter 440 located between ananode 450 and a common cathode 460 a. The first ultrasonic transducercomprises a flexible low frequency ultrasound emitter 430 a locatedbetween the cathode 460 a (common cathode with the light source) and acommon anode 470. The second ultrasonic transducer comprises a flexiblehigh frequency ultrasound emitter 430 b located between a cathode 460 band the anode 470 (common anode with the low frequency ultrasoundemitter). Various power sources are provided so that DC or pulsed DC isused to power the light source, while AC is used to power each of theultrasonic transducers.

In this exemplary embodiment, the flexible light emitter 440 comprisesan OLED or printable LEDs, and the flexible low frequency 430 a and highfrequency 430 b ultrasound emitters each comprise PiezoPaint™ material(Meggitt PLC) (i.e., the same material is driven at differentfrequencies). An ultrasound reflective layer 475 is located above theultrasonic transducers, i.e., between the surface of the device facingaway from the skin and the ultrasonic transducers, to direct theultrasound towards the patient's skin. The ultrasound reflective layer475 is comprised of ceramic. The anode 470 and cathodes 460 a and 460 bare each comprised of a conductive metal such as silver. The devicefurther includes a matching layer 435 located between the ultrasonictransducers and the skin. The matching layer 435 has graphene 435 aformed therein to serve as a flexible heater layer. The graphene 435 amay also serve as an electrical stimulation layer for iontophoresis.

The anode 450, substrate 420, and matching layer 435 with graphene 435 aare all transparent. The substrate 420 is comprised of a transparentsilicon rubber, and also serves as a matching layer for the ultrasound.The anode 450 is comprised of ITO. Light generated from the flexiblelight emitter 440 is emitted through the transparent anode 450,substrate 420 and matching layer 435 with graphene 435 a such that thedevice has a “bottom” light emitting configuration. A therapeutic and/orcosmetic composition as described above may be placed between thematching layer 435 with graphene 435 a and the patient's skin.

Fifth Exemplary Embodiment

FIG. 8 illustrates a fifth exemplary embodiment of the device of thepresent invention. The device 510 comprises a light/transducer structure(e.g., having a layered configuration as illustrated in one of the priorembodiments), along with a matching layer 535 and a transparent negativeelectrode that serves as an electrical stimulation layer 595 a forproviding optional electrical stimulation to the patient. The electricalstimulation layer is electrically coupled to a positive return electrode595 b applied to the surface of the skin at a separate location.Electrical current flows from a power source to the positive returnelectrode 595 b and through the patient's skin to the negative electrode595 a. The current is preferably a DC current of about 1 to 10 mA (e.g.,about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mA) with about 2 to 4 mA beingmost preferred. The voltage is typically 100 V or less (e.g., about 100,90, 80, 70, 60, 50 or 40 V or less). A therapeutic and/or cosmeticcomposition 500 as described above is placed between the electricalstimulation layer 595 a and the patient's skin.

Sixth Exemplary Embodiment

FIG. 9 illustrates a sixth exemplary embodiment of the device of thepresent invention wherein, for simplicity, the various layers/componentsof the device are shown in a non-staggered stacked arrangement. Thedevice 610 comprises a light source formed above a transparent substrate620, which also functions as a matching layer as described below. Twoultrasonic transducers are formed above the light source. The lightsource comprises a flexible light emitter 640 located between an anode650 and a common cathode 660 a. The first ultrasonic transducercomprises a flexible high frequency ultrasound emitter 630 b locatedbetween the cathode 660 a (common cathode with the light source) and acommon anode 670. The second ultrasonic transducer comprises a flexiblelow frequency ultrasound emitter 630 a located between a cathode 660 band the anode 670 (common anode with the high frequency transducer).Various power sources are provided so that DC or pulsed DC used to powerthe light source, while AC is used to power each of the ultrasonictransducers.

In this exemplary embodiment, an ultrasonic absorptive layer 677 islocated above the ultrasonic transducers, i.e., between the surface ofthe device facing away from the skin and the ultrasonic transducers, toabsorb ultrasound in that direction. The common anode 670 and cathodes660 a and 660 b are each comprised of a conductive metal such as silver.As noted above, the substrate 620 located between the ultrasonictransducers and the skin also serves as a matching layer. Thesubstrate/matching layer 620 has graphene 620 a formed therein to serveas a heater layer. Further, the device includes a positive electrodethat serves as an electrical stimulation layer 695 a for providingoptional electrical stimulation to the patient. The electricalstimulation layer 695 a is electrically coupled to a negative returnelectrode 695 b applied to the surface of the skin at a separatelocation. Electrical current flows from a power source to the positiveelectrode 695 a and through the patient's skin to the negative returnelectrode 695 b. An insulating layer 693 may be provided between thesubstrate/matching layer 620 with graphene 620 a and the electricalstimulation layer 695 a. A therapeutic and/or cosmetic composition 600as described above is placed between the electrical stimulation layer695 a and the patient's skin.

In this exemplary embodiment, the flexible light emitter 640 comprisesan OLED or printable LEDs, and the flexible low and high frequencyultrasound emitters 630 a, 630 b each comprise PiezoPaint™ material(Meggitt PLC) (i.e., the same material is driven at differentfrequencies). The anode 650, substrate/matching layer 620 with graphene620 a, insulating layer 693 and electrical stimulation layer 695 a areall transparent. The anode 650 is comprised of ITO. Thesubstrate/matching layer 620 is comprised of a transparent siliconrubber. The insulating layer 693 is formed of transparent silicon, andthe electrical stimulation layer 695 a is formed of conductivetransparent silicon, graphene, or transparent silver fiber. Lightgenerated from the flexible light emitter 640 is emitted through thetransparent anode 650, substrate/matching layer 620 with graphene 620 a,insulating layer 693 and electrical stimulation layer 695 a such thatthe deviced has a “bottom” light emitting configuration.

Also, in this exemplary embodiment, a flexible printed circuit board(PCB) 697 is printed on the surface of the device facing away from thepatient's skin. The flexible PCB 697 contains the electrical componentsshown generally in FIG. 14, including the microcontroller (with drivecircuits for the light source, ultrasonic transducers, and electricalstimulation layer), the wireless communication module (e.g., Wi-Fi orBluetooth), the sensor electronics. The flexible PCB 697 is electricallycoupled to a photo sensor in contact with the patient's skin. The lightsource pulses the patient's skin with purple light (e.g., 415 nm) andthe photo sensor measures the presence of acne bacterium by detectingred light (e.g., 630 nm) given off by acne bacterium. The feedbackprovided by the photo sensor is used by the flexible PCB 697 to vary orterminate the dose based on the bacterial kill rate.

Seventh Exemplary Embodiment

FIG. 10 illustrates a seventh exemplary embodiment of the device of thepresent invention. The device 710 comprises a light source formed abovea transparent substrate 720 and a dual frequency ultrasonic transducerformed above the light source (i.e., a dual frequency transducer with aunimorph design, as discussed above). The light source comprises aflexible light emitter 740 located between an anode 750 and a commoncathode 760. The dual frequency ultrasonic transducer comprises aflexible ultrasound emitter 730 bonded to a metal substrate 760 asdescribed in Galluzzo et al., U.S. Published Patent Application No.2012/0267986. The metal substrate 760 functions as the cathode for theflexible ultrasound emitter 730 (common cathode with the light source)and an anode 770 is also provided. Various power sources are provided sothat DC or pulsed DC is used to power the light source, while AC is usedto power the dual frequency ultrasonic transducer. For simplicity, thepower sources and wiring are not shown. Further, a transparent barrierlayer 780 protects the flexible light emitter 740 from moisture andoxygen.

In this exemplary embodiment, the flexible light emitter 740 comprisesan OLED or printable LEDs, and the flexible ultrasound emitter 730comprises PiezoPaint™ material (Meggitt PLC) (which can function as adual frequency transducer with a unimorph design). Both the substrate720 and the anode 750 are transparent. The substrate is comprised of atransparent silicon rubber, and also serves as a matching layer for theultrasound. The anode 750 is comprised of ITO. Light generated from theflexible light emitter 740 is emitted through the transparent anode 750and substrate 720 such that the device has a “bottom” light emittingconfiguration. The metal substrate 760 (common cathode to the lightsource and transducer) is made of stainless steel, and the anode 770 iscomprised of a conductive metal such as silver. The barrier layer iscomprised of Flexent film (Konica Minolta). A therapeutic and/orcosmetic composition as described above is placed between the substrate720 and the patient's skin.

Eighth Exemplary Embodiment

FIG. 11 illustrates an eighth exemplary embodiment of a light/ultrasonictransducer system 800 in accordance with the present invention. Thelight/ultrasonic transducer system 800 comprises a plurality of devices810 a-810 f each of which may be configured in accordance with any oneof the previous exemplary embodiments. The devices are arranged in anarray and held in proximity to each other by a flexible, preferablytransparent, material 812, such as a silicon or plastic, or otherpolymer. In this exemplary embodiment, six devices are generallyillustrated. However, it will be appreciated that the system may includeany number of devices (e.g., 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40,50, etc.) arranged in an array. The devices are individually connectedto one or more power sources (not shown). It should be noted that eacharray element could have different output parameters for the ultrasoundand light based on sensing information recorded from the tissueunderlying each section of the array.

The devices 810 a-810 f may be the same or different, for example interms of the shape, size, light output and/or ultrasonic output. Thedevices may emit light of different wavelengths, intensities, durations,duty factors, and modulation frequencies. The devices may produceultrasound of different frequencies, power densities, modulationfrequencies, and duty factors. Each of the devices may be independentlycontrolled by a microcontroller, and, each light source and/orultrasonic transducer within each of the devices may be independentlycontrolled by the microcontroller. As such, each of the devices iscapable of delivering light and/or ultrasound simultaneously orsequentially or separately.

While the present invention has been described and illustratedhereinabove with reference to several exemplary embodiments, it shouldbe understood that various modifications could be made to theseembodiments without departing from the scope of the invention.Therefore, the present invention is not to be limited to the specificconfiguration and methodology of the exemplary embodiments, exceptinsofar as such limitations are included in the following claims.

What is claimed and desired to be secured by Letters Patent is asfollows:
 1. A flexible device having a layered structure for deliveringelectrical stimulation, light and ultrasound to a skin surface,comprising: a plurality of flexible conductive layers configured toconnect to a power source, wherein the flexible conductive layerscomprise a first conductive layer, a second conductive layer, and athird conductive layer; (a) a flexible light emitter layer positionedbetween the first conductive layer and the second conductive layer,wherein the flexible light emitter layer comprises a layer of printedlight emitting diodes configured to emit light when driven by the powersource, wherein the layer of printed light emitting diodes comprises aplurality of individual light emitting diodes suspended and dispersed ina liquid or gel so as to form a diode ink that is printed on one of thefirst and second conductive layers and wherein the other of the firstand second conductive layers is applied over the diode ink, wherein thefirst conductive layer comprises a transparent conductive layer suchthat the light passes through the transparent conductive layer to theskin surface and (b) a flexible ultrasound emitter layer positionedbetween the second conductive layer and the third conductive layer,wherein the flexible ultrasound emitter layer is configured to produceultrasound when driven by the power source; and a flexible electricalstimulation layer configured to connect to the power source, wherein theflexible electrical stimulation layer is configured to function as anelectrode and provide electrical stimulation when driven by the powersource.
 2. The device of claim 1, wherein the flexible electricalstimulation layer is configured to function as one of the flexibleconductive layers.
 3. The device of claim 1, wherein the flexibleelectrical stimulation layer is transparent such that the light passesthrough the flexible electrical stimulation layer to the skin surface.4. The device of claim 1, wherein the electrical stimulation provided bythe flexible electrical stimulation layer is configured toiontophoretically deliver a charged therapeutic or cosmetic compositionthrough the skin surface.
 5. The device of claim 1, wherein theelectrical stimulation provided by the flexible electrical stimulationlayer is configured to decrease muscle spasms.
 6. The device of claim 1,wherein the electrical stimulation provided by the flexible electricalstimulation layer is configured to decrease muscle tone for thetreatment of muscle hypertonicity.
 7. The device of claim 1, wherein theelectrical stimulation provided by the flexible electrical stimulationlayer is configured to increase muscle tone for the treatment of musclehypotonicity.
 8. The device of claim 1, wherein the electricalstimulation provided by the flexible electrical stimulation layer isconfigured to provide electroanesthesia.
 9. The device of claim 1,wherein one or both of the light emitted by the flexible light emitterlayer and the ultrasound produced by the flexible ultrasound emitterlayer is configured to cause transdermal transport of a therapeutic orcosmetic composition through the skin surface.
 10. The device of claim1, wherein the flexible ultrasound emitter layer comprises apiezoelectric coating.
 11. The device of claim 1, wherein the flexibleultrasound emitter layer is configured to produce one or both of lowfrequency ultrasound at a frequency in the range of 20 kHz to 500 kHzand high frequency ultrasound at a frequency in the range of 500 kHz to20 MHz.
 12. The device of claim 1, further comprising a flexible heaterlayer.
 13. The device of claim 1, further comprising a flexible printedcircuit board layer.
 14. The device of claim 1, further comprising aflexible acoustic matching layer.
 15. The device of claim 1, wherein thedevice is flexible and configured to form a non-planar contact surfaceagainst the skin surface.
 16. The device of claim 1, wherein the deviceis conformable to the skin surface.
 17. A system for deliveringelectrical stimulation, and one or both of light and ultrasound to askin surface, comprising: the flexible device of claim 1; and a flexibledevice comprising: a plurality of flexible conductive layers configuredto connect to a power source, wherein the flexible conductive layerscomprise a first conductive layer, a second conductive layer, and athird conductive layer; (a) a flexible light emitter layer positionedbetween the first conductive layer and the second conductive layer,wherein the flexible light emitter layer comprises a layer of printedlight emitting diodes configured to emit light when driven by the powersource, wherein the layer of printed light emitting diodes comprises aplurality of individual light emitting diodes suspended and dispersed ina liquid or gel so as to form a diode ink that is printed on one of thefirst and second conductive layers and wherein the other of the firstand second conductive layers is applied over the diode ink, wherein thefirst conductive layer comprises a transparent conductive layer suchthat the light passes through the transparent conductive layer to theskin surface and (b) a flexible ultrasound emitter layer positionedbetween the second conductive layer and the third conductive layer,wherein the flexible ultrasound emitter layer is configured to produceultrasound when driven by the power source; a flexible electricalstimulation layer configured to connect to the power source, wherein theflexible electrical stimulation layer is configured to function as anelectrode and provide electrical stimulation when driven by the powersource; and an electronic circuit electrically coupled to the flexibledevice, wherein the electronic circuit comprises a controller operableto control the flexible device.
 18. The system of claim 17, wherein thecontroller is electrically coupled to at least one sensor in contactwith the skin surface, wherein the controller is operable to receivesensor data from the sensor and dynamically control the flexible devicein response to the received sensor data.
 19. The system of claim 17,wherein the controller is electrically coupled to a communication modulethat enables wired or wireless communication with an external controldevice.
 20. The system of claim 19, wherein the external control deviceis operable to execute a control application for externally controllingthe controller.
 21. The system of claim 19, wherein the external controldevice is operable to communicate with a remote server.
 22. The systemof claim 17, further comprising a therapeutic or cosmetic compositionconfigured to be applied to the skin surface.
 23. The system of claim22, wherein the composition is in the form of a gel, cream or ointment,or a pad incorporating a gel, cream or ointment.
 24. The system of claim22, wherein the composition is contained in a hydrogel pad.
 25. Thesystem of claim 22, wherein the composition includes a conductive ionicmolecule or compound.
 26. The system of claim 25, wherein the electricalstimulation provided by the flexible electrical stimulation layer isconfigured to iontophoretically deliver the conductive ionic molecule orcompound through the skin surface.
 27. The system of claim 26, whereinthe conductive ionic molecule or compound is positively charged, andwherein the power source is configured to connect to the flexibleelectrical stimulation layer and a return electrode such that theflexible electrical stimulation layer is configured to function as apositive electrode and the return electrode is configured to function asa negative electrode.
 28. The system of claim 26, wherein the conductiveionic molecule or compound is negatively charged, and wherein the powersource is configured to connect to the flexible electrical stimulationlayer and a return electrode such that the flexible electricalstimulation layer is configured to function as a negative electrode andthe return electrode is configured to function as a positive electrode.29. The system of claim 22, wherein the composition includes one or moreof low or high molecular weight hyaluronic acid, ascorbic acid (vitaminC) or alpha-tocopherol (vitamin E) or their derivatives or theirpharmaceutically acceptable salts and esters.
 30. The system of claim29, wherein one or both of the light emitted by the flexible lightemitter layer and the ultrasound produced by the flexible ultrasoundemitter layer is configured to cause transdermal transport of thecomposition through the skin surface.
 31. The system of claim 17,wherein the power source is operable to generate a current to drive theflexible electrical stimulation layer, wherein the current comprises oneof a direct current, an alternating current, a pulsed direct current, ora direct current superimposed with one of an alternating current or apulsed direct current.
 32. The system of claim 17, wherein the powersource is operable to generate a current to drive the flexible lightemitter layer, wherein the current comprises one of a direct current ora pulsed direct current.
 33. The system of claim 17, wherein the powersource is operable to generate a current to drive the flexibleultrasound emitter layer, wherein the current comprises an alternatingcurrent.
 34. The system of claim 17, further comprising a returnelectrode configured to be applied to the skin surface at a locationseparate from the device, wherein the power source is configured to beconnected to the flexible electrical stimulation layer and the returnelectrode so as to provide the electrical stimulation.
 35. The system ofclaim 17, further comprising a return electrode incorporated into theflexible device, wherein the power source is configured to be connectedto the flexible electrical stimulation layer and the return electrode soas to provide the electrical stimulation.
 36. The system of claim 17,wherein the electrical stimulation provided by the flexible electricalstimulation layer is configured to decrease muscle spasms.
 37. Thesystem of claim 17, wherein the electrical stimulation provided by theflexible electrical stimulation layer is configured to decrease muscletone for the treatment of muscle hypertonicity.
 38. The system of claim17, wherein the electrical stimulation provided by the flexibleelectrical stimulation layer is configured to increase muscle tone forthe treatment of muscle hypotonicity.
 39. The system of claim 17,wherein the electrical stimulation provided by the flexible electricalstimulation layer is configured to provide electroanesthesia.
 40. Thesystem of claim 17, wherein the flexible ultrasound emitter layercomprises a piezoelectric coating.
 41. The system of claim 17, whereinthe device is conformable to the skin surface.
 42. A flexible devicehaving a layered structure for delivering electrical stimulation, lightand ultrasound to a skin surface, comprising: a plurality of flexibleconductive layers configured to connect to a power source, wherein theflexible conductive layers comprise a first conductive layer, a secondconductive layer, and a third conductive layer; (a) a flexible lightemitter layer positioned between the first conductive layer and thesecond conductive layer two, wherein the flexible light emitter layercomprises one of an organic light emitting diode or a plurality ofprinted light emitting diodes comprising a plurality of individual lightemitting diodes suspended and dispersed in a liquid or gel so as to forma diode ink that is printed on one of the flexible conductive layers,wherein the flexible light emitter layer is configured to emit lightwhen driven by the power source, wherein the first conductive layercomprises a transparent conductive layer such that the light passesthrough the transparent conductive layer to the skin surface and (b) aflexible ultrasound emitter layer positioned between the secondconductive layer and the third conductive layer, wherein the flexibleultrasound emitter layer is configured to produce ultrasound when drivenby the power source; and a flexible electrical stimulation layerconfigured to connect to the power source, wherein the flexibleelectrical stimulation layer is configured to function as an electrodeand provide electrical stimulation when driven by the power source. 43.The device of claim 42, wherein the flexible electrical stimulationlayer is transparent such that the light passes through the flexibleelectrical stimulation layer to the skin surface.
 44. The device ofclaim 42, wherein at least one of the flexible conductive layerscomprises a transparent conductive layer such that the light passesthrough the transparent conductive layer to the skin surface.
 45. Thedevice of claim 42, wherein the flexible ultrasound emitter layercomprises a piezoelectric coating.
 46. A flexible device having alayered structure for delivering electrical stimulation, light andultrasound to a skin surface, comprising: a plurality of flexibleconductive layers configured to connect to a power source, wherein theflexible conductive layers comprise a first conductive layer, a secondconductive layer, a third conductive layer, and a fourth conductivelayer; (a) a flexible light emitter layer positioned between the firstconductive layer and the second conductive layer, wherein the flexiblelight emitter layer comprises one of an organic light emitting diode ora plurality of printed light emitting diodes comprising a plurality ofindividual light emitting diodes suspended and dispersed in a liquid orgel so as to form a diode ink that is printed on one of the flexibleconductive layers, wherein the flexible light emitter layer isconfigured to emit light when driven by the power source, wherein thefirst conductive layer comprises a transparent conductive layer suchthat the light passes through the transparent conductive layer to theskin surface and (b) a flexible ultrasound emitter layer positionedbetween the third conductive layer and the fourth conductive layer,wherein the flexible ultrasound emitter layer is configured to produceultrasound when driven by the power source; and a flexible electricalstimulation layer configured to connect to the power source, wherein theflexible electrical stimulation layer is configured to function as anelectrode and provide electrical stimulation when driven by the powersource.